Anilides



United States Patent Ofiice Patented Sept. 12, 1967 3,341,584 ANILIDESAubrey A. Larsen and Robert H. Uloth, Evansville, Ind., assignors toMead Johnson & Company, Evansviile, Ind., a corporation of Indiana NoDrawing. Filed Mar. 11, 1965, Ser. No. 439,086 28 Claims. (Cl. 260-556)Formula I In the above formula X represents a substi-tuent which may behydrogen, hydroxy, amino, lower alkoxy, benzyloxy, halogen, lower alkyl,or the group R SO NH, R and R are independently selected from loweralkyl, phenyl, or substituted phenyl, and Z is C=O or CHOH. The phenylsubstituent may be lower alkyl, halogen, lower alkoxy, or benzyloxy. Alkis an alkylene group having 1 to 4 carbon atoms joining Z and throughfrom 1 to 2 carbon atoms.

The symbol represents an N-substituted heterocyclic group having up to 7carbon atoms or an N-substituted heteropolycyclic group having up to 11carbon atoms in which the nitrogen atom is part of the heterocyclicring. The symbol I CH era-@s OzNH I t/goom a CH; I CHSO CHzO When usedherein the terms lower alkyl and lower alkoxy are intended to includethose containing up to four carbon atoms such as methyl, ethyl,n-propyl, isopropyl, butyl, secondary butyl, isobutyl, and tertiarybutyl. The groups ZAlkNR R and X may be located in any of the o, m, or ppositions of the sulfonanilide ring. They may be either adjacent orseparated.

The sulfonanilides of Formula I wherein Z is CHOH are pharmacologicallyactive phenethanolarnines having actions which either resemble theeffects of the adrenal medullary hormones or adrenergicneurotransmitters or oppose the effects of the adrenal medullaryhormones or adrenergic neurotransmitters. Some have papaverine-likesmooth muscle depressant activity. They have the advantages of lowertoxicity and a novel selectivity of action which largely frees them fromthe side effects associated with administration of priorphenethanolamides. In the case of their phenolic and aminophenethanolamine counterparts, they have the added advantages of greaterstability and of being better absorbed on oral administration. In oneaspect the present invention involves the discovery that alky andaryl-sulfonamido nuclearly substituted phenalkanolamines have usefulpharmacologic effects, suiting them variously as vasopressors,vasodepressors, analgesics, bronchodilators, a-receptor stimulants,fi-receptor stimulants, u-receptor blocking agents, S-receptor blockingagents, papaverine-like smooth muscle depressants, or anti-inflammatoryagents useful in controlling or preventing anaphylaxis. The specificdosage varies from one member of the series to another, with the subjectand condition being treated, and with the particular pharmacologicaleffect sought. In general, dosages fall in the range of 0.1 mcg. to 20mg. per kilogram of body weight.

A number of the substances of Formula I wherein Z is C=O also havepharmacological utility. Of particular interest in this regard are3-(Z-benzylmethylaminoacetyl) methanesulfonanilide and 4 (2dibenzylaminoacetyl) methanesulfonanilide which have effects on thecentral nervous system, and 3-(2-aminoacetyl)methanesulfonanilide whichis pressor agent having long duration of action. These substances may beadministered by the oral route in doses of 0.35 to 25 mg./kg. of bodyweight depending upon the host and condition being treated.

Intermediates useful for preparing the substances of Formula I aredefined by Formula II below. In this formula A represents a chlorine,bromine, or iodine atom, Y may be hydrogen, halogen, hydroxy, nitro,lower alkoxy, benzyloxy, lower alkyl, or R SO NH, and R R Alk, R and Rhave the same meaning as in Formula I.

The intermediates of Formula II are haloalkyl ketones which aretransformed into substances of Formula III by reaction with anappropriate amine as illustrated below. In some instances furtheroperations to provide the desired nuclear substituents after introducingthe R R N- amino group are convenient, for instance when X is to be NHor R SO NH in the end product.

NHSOzR IIIHSOZR R R5 CO-Alk-A HN\ C OAlkN\ R Formula II Formula III Thesubstances ofFormula III or Formula I wherein Z is C=O comprise afurther class of intermediates which are converted to thephenalkanolamines of Formula I wherein Z is CHOH by catalytic orchemical reduction. The latter is of the widest general applicability,and particularly in those instances when the benzene ring of the endproduct is to contain a catalytic hydrogenation sensitive group as willbe obvious to those skilled in the art.

The above process is of perhaps the widest applicability throughout theseries since a great variety of the present substances can be obtainedby using various amines,

A second method of general applicability is to react substituted anilineof Formula IV with an appropriate sulfonyl halide or sulfonic anhydride.Again Y, R, R Alk, R and R have the same meaning as above.

H /R (R S O2)z0 C-Alk-N R S 0201 Y Formula IV NH S 0213.

O E II CAlkN Formula III The latter method is useful since variouscompounds of the present invention can be prepared from the sameintermediate by use of different sulfonyl halides or anhydrides.

It will be apparent to those skilled in the art that the carbinol groupof Formula I (Z is CHOH) is an asymmetric carbon atom. In thosecarbinols in which Alk does not contain an additional asymmetric carbonatom, two enantiomorphic forms thereof exist. With those carbinols ofFormula I where Alk contains an asymmetric carbon atom in addition tothe carbinol group, two racemic modifications of the product exist eachof which consists of a pair of enantiomorphic forms. stereoisomericforms of the substances of Formula I are included within the scope ofthe present invention.

The compounds of Formula I are amphoteric substances, forming salts withboth acids and bases. These salts are also considered part of thepresent invention and it is intended to include not only thepharmaceutically acceptable salts which have the physiological usesreferred to above, but also other salts, since they have utility asintermediates cally preferred forms of the present products, includingthe free base. For example, acid addition salts with optically activeacids such as D-camphorsulfonic acid, L- or D-tartaric acid are usefulfor resolution of enantiomorphic pairs of the present compounds and areconsidered part of this invention.

Examples of pharmaceutically acceptable acid addition salts include thehydrochloride, hydrobrornide, acetate, propionate, phosphate, nitrate,succinate, gluconate, mucate, sulfate, methanesulfonate,ethanesulfonate, p-toluensulfonate, etc. salts. Pharmaceuticallyacceptable metal salts include the sodium, potassium, lithium,magnesium, calcium, barium, zinc, and aluminum salts. The sulfonanilidefree bases of Formula I are also pharmaceutically acceptable forms.

The present salts may be prepared in conventional fashion by treatmentof one of the present compounds with an acid or base. For thepreparation of salts with monobasic acids and monoacidic bases,use ofequimolar quantities of the mation of salts of polyacidic bases andpolybasic acids, it is convenient to reduce the molecular proportion ofthe acid or base so that but one chemical equivalent thereof isemployed.

A particularly preferred compound of the present invention is3-(2-methylamino-l-hydroxyethyl)methanesulfonanilide. It has strong andselective adrenergic vasoconstrictor activity of moderately longduration. It is effective on oral administration. Its actions areexerted on mammalian hosts through activation of a-adrenergic receptors,desirable central and cardiac effects of prior phenethanolamines. It isthought to be the most selective of all known adrenergic agents in thisrespect. It is particularly All of these and other in preparation ofpharmaceutitwo reactants is convenient. Inthe .fori and as a result itis free of many of the un-.

suited as a systemic vasoconstrictor for use in Surgery to reducebleeding, in relief of shock, and as a nasal decongestant. It is usefulin ophthalmic dosage forms.

As a nasal decongestant,3-(Z-methylamino-l-hydroxyethyl)methanesulfonanilide may be appliedtopically or systemically, preferably by the oral route. Its advantagesinclude failure for the development of tolerance to its action to occuron repeated usage, lack of stimulating elfect on the central nervoussystem, lack of irritating propensity, lack of local anesthetic action,and lack of so-called rebound or secondary dilator effects when appliedtopically.

For nasal use, solutions having concentrations ranging from 0.05 to 0.5%may be employed, 0.1 to 0.25% solutions being preferred. An isotonicsolution is generally desirable for such preparations, physiologicsaline being quite satisfactory. In addition it is desirable for suchpreparations to contain a preservative to prevent microbiological growththerein during periods of non-use after the bottle is put into use.Suitable preservatives include the parabens to reduce yeast and moldgrowth and an antibacterial agent such as thimerosal or benzalkoniumchloride. For ophthalmic use buffered sterile solutions havingconcentrations in the range 0.5 to 5.0% are applicable.

As a systemic vasoeonstrictor, oral, or parenteral doses in the range of70 meg/kg. of body weight up to 20 mg./kg. of body weight of the subjectare recommended. Pharmaceutically acceptable salts of3-(2-methylamino-lhydroxyethyl)methanesulfonanilide including metal andacid addition salts thereof possess equivalent pharmacologicalproperties to the parent substance. The preferred dosage unit contains0.1 to mg. of 3-(2-methylaminol-hydroxyethyl)methanesulfonanilide or aproportionate amount of a pharmaceutically acceptable acid addition ormetal salt thereof.

These substances, and indeed each of the therapeutic agents of thepresent invention, may be prepared in various types of dosage unitformulations including tablets, capsules, elixirs, solutions,suspensions, ointments, etc., using various types of excipients,preservatives, tablet lubricants, and carriers including both solids andliquids such as corn starch, lactose, calcium phosphate, stearic acid,polyethylene glycol, Water, sesame seed oil, peanut oil, propyleneglycol, etc. They may be administered orally, parenterally, ortopically.

Pharmaceutical formulations of the present invention may be compoundedwith one of the novel sulfonanilides disclosed and claimed herein as thesole active ingredient or they may include other additional activeingredients, including tranquilizers, sedatives, analeptics, analgesics,antipyretics, hypnotics, antibiotics, such as polymixin, tyrothrycin,grammacidin, tyrocidin, and neomycin, antihistamines such aschlorprophenpyridamine maleate or methdilazine hydrochloride,anti-inflammatory agents such as cortisone phosphate, a surfactant, achemical antiseptic such as thimerasol, benzalkonium chloride, or amucolytic agent such as tyloxypal.

The experimental description which follows concerns the preparation of anumber of specific compounds of the present invention with directionsfor their application to the preparation of other members of the series.Typical pharmaceutical formulations are also illustrated.

PROCEDURE 1 3 (acetyl)methanesulfonanilide. Methanesulfonyl chloride,114.6 g. (1.0 mole) is added dropwise during a period of 3 to 4 hours toa stirred solution of 3-aminoacetophenone, 135.2 g. (1.0 mole) in 90 ml.of pyridine While maintaining the temperature at 25-30 C. with externalcooling. After stirring overnight, the reaction mixture is poured into 1l. of ice and Water and acidified with concentrated hydrochloric acid.Extraction of the acid solution with chloroform (3x500 ml.) and evapora.tion of the extracts yields 172.8 g. (81%) of a tan solid, M.P. 73-87 C.This product is purified by first crystallizing it from water, 3.5 1.,with treatment of the aqueous solution prepared in the course thereofwith pulverized charcoal, and then twice recrystallizing fromisopropanol, 8 ml. per gram of solid, alfording 104 g. (49%) of whiteneedles, M.P. 97-98 C. A second crop of product weighing 28.5 g. isobtained by concentration of the isopropanol filtrate, M.P. 95.598.5 C.

Analysis-C, 50.89; H, 5.10; N, 6.38; S, 14.94.

By submitting various sulfonyl halides to Procedure 1, othersulfonanilides are prepared which are useful in the present invention.Various representative sulfonyl halides useful in this fashion and theresulting acetyl sulfonanilides are listed in Table I.

TABLE I.REPRESENTATIVE ALKYL- AND ARYLSULFONANILIDES Sullonyl HalideAcetylsulfonanilide R Ethanesulfonyl chloride 3-(aeety1)ethanesullonanilide. n-Butanesullonyl chloride-3-(acetyl)butanesulfonanilide.

Benzenesulfouyl chloride. 3-(acetyl)benzcnesulfonanilide.p-Toluenesulfonyl chloride 3-(acetyl)-p-toluenesnlionanilide.

m-Aminopropiophenone and 3-chloro-4-aminoacetophenone (J. Org. Chem. 12,681 (1949)) are converted by means of Procedure 1 into3-(propionyl)methanesulfonanilide and2-chloro-4-acetylmethanesulfonanilide respectively, which are in turnuseful in the present invention as described hereinafter.

Z-methanesulfonamido 4(Z-methylamino-l-hydroxyethyl)methanesulfonanilide hydrochloride isproduced by application of Procedure 1 to2-amino-4-(2-benzylmethylaminoacetyl) methanesulfonanilide and reductionof the resulting product according to Procedure 16. The above namedamino compound is obtained by stannous chloride reduction (Procedure 27)of 2-nitro-4-(Z-benzylmethylaminoacetyl)methanesulfonanilide (Table VI,10th entry).

PROCEDURE 2 4 -hydr0xy-3-nitr0acet0phenone.-The procedure for thenitration of 4-hydroxyacetophenone described by Bartlett andTrachtenberg (J. Am. Chem. Soc. 80, 5808 (1958)) is employed; yield M.P.128-131 C,

PROCEDURE 3 4-hydroxy-3-nitr0pr0pi0phen0ne.-The procedure of Bartlettand Trachtenberg for the preparation of 4- hydroxy-3-nitroacetophenonereferred to above is used for the nitration of 4-hydroxypropiophenone;yield 86%; M.P. 67-70 C.

PROCEDURE 4 4-benzyloxy-3-nitroacetophenone.A mixture of 36.2 g. (0.2mole) of 4-hydroXy-3-nitroacetophenone; 28.0 g. (0.2 mole) of benzylchloride, 22 ml. of 56% aqueous potassium hydroxide solution (0.22mole); 2 g. of sodium iodide; 200 ml. of water; and 300 ml. of ethanolis stirred and refluxed for 48 hrs. The ethanol is removed bydistillation at reduced pressure, and the resulting aqueous mixture isfiltered. The filter cake is washed with water and air dried; yield 43.2g. (80% M.P. C. After recrystallization from a' Z-butanoneisopropylalcohol mixture, the material melts at 134- 137 C. when heated in acapillary tube.

PROCEDURE 5 tube PROCEDURE 6 3 amino 4 benzyl0xyacet0phen0ne.A mixtureof 13.6 g. (0.05 mole) .of 4-benzyloxy-3-nitroacetophenone, 10 to 15 g.of aged Raney nickel catalyst, and 1 l. of

methanol is hydrogenated at room temperature and atmospheric pressureuntil an amount of hydrogen calculated to reduce the nitro group hasbeen absorbed. The reaction mixture is filtered under a nitrogenatmosphere into an ethanolic solution of hydrogen chloride. The ethanolis removed by distillation at reduced pressure and the residue mixedwith Z-butanone. The precipitated solid is collected on a filter, yield,11.7 g. (84%); M.P. 18L- 184 C. The free base is prepared by treatmentof this material with an excess of 10% aqueous sodium hydroxide;recrystallized from isopropyl alcohol, M.P. 130- 132 C.

PROCEDURE 7 3 amino 4 ben-zyloxypropiophenne.-4-benzyloxy-4-nitropropiophenone is hydrogenated employing a Raney nickel catalystaccording to the method of Procedure 6; product recrystallized fromisopropyl alcohol, M.P. 127-129 C.

PROCEDURE 8 acetyl 2 benzyloxymethanesulf0nanilide.--Methanesulfonylchloride, 4.4 g. (0.039 mole), is added dropwise to a cooled solution of10.7 g. (0.039 mole) of 3- amino-4-benzyloxyacetophenone hydrochloridein 50 ml. of pyridine. The reaction mixture is stirred for 4 hrs. atroom temperature and then poured into 500 ml. of water. The resultingprecipitate is collected on a filter, yielding 10.6 g. of the salt ofthe desired substance with 3- amino-4-benzyloxyacetophenone;recrystallized from isopropyl alcohol the material melts at 108-110 C.The salt is decomposed and the unreacted 3-amino-4-benzyloxyacetophenoneseparated therefrom by treatment of the salt with an excess of aqueoussodium hydroxide (e.g. 25 ml. per gram of salt). The precipitatedmaterial is removed by filtration, and the desired product is recoveredfrom the filtrate by acidification with concentrated hydrochloric acid.The resulting precipitate is collected, washed with water, dried, andrecrystallized from isopropyl alcohol; M.P. 142144 C.

PROCEDURE 9 2 chloro 5 acetylmethanesulfonanilide.4 chloroacetophenoneis nitrated and the resulting nitro compound is then reduced to3-amino-4-chloroacetophenone according to the method described in J.Org. Chem. 12, 692 (1947). This material is then converted to thecorresponding methanesulfonanilide by treatment with methanesulfonylchloride and pyridine according to Procedure 1.

PROCEDURE 10 4-(2 bromoacetyl)methanesulfonanilide.-Aluminurn chloride,40 g. (0.3 mole), is added in small portions during min. to a mixture of17.1 g. (0.1 mole) of methanesulfonanilide, 35.6 g. (0.177 mole) ofbromoa-cetyl bromide, and 75 ml. of carbon disulfied. Evolution ofhydrogen bromide from the reaction becomes quite apparent during thecourse of the addition. A two-phase liquid system results which isrefluxed for /2hr. and then stirred at room temperature for anadditional hour. The upper layer (CS is then decanted from the extremelyviscous lower layer. The latter is then mixed with 200 g. of icecontaining 7 ml. of concentrated hydrochloric acid. A brown solidseparates which is collected on a filter. It is washed on the filter inturn with water, ethanol, and ether to yield the product as a tan solid,weighing 26.5 g. (90.3%), M.P. 161-171 C. (dec.). It is recrystallizedseveral times from ethanol to yield the product in analytically purecondition, M.P. 185-187 C. (dec.).

Analysis.-Br, 27.35; N, 4.85; S, 11.01.

PROCEDURE 11 2-benzyl0xymethanesulf0nanilide.--A mixture of 40.2 g. of2-hydroxyacetanilide, 28.0 (0.2 mole) of benzyl chloride, 22 ml. of 56%aqueous potassium hydroxide solution (0.22 mole), 2 g. of sodium iodide,200 ml. of water, and 300 ml. of ethanol is refluxed with stirring for48 hrs. The 2-benzyloxyacetanilide which results from this process isrecovered from the reaction mixture by distilling the ethanol therefromat reduced pressure and collecting the precipitate on a filter. Thismaterial is then hydrolyzed with aqueous sodium hydroxide to provide2-benzyloxy aniline. The latter is then treated with methanesulfonylchloride under the conditions of Procedure 1 to provide2-benzyloxymethanesulfonanilide.

PROCEDURE 12 N,N-0-phenylene-bis-methanesulf0nanilide.-This substance isprepared by acylation of o-phenylenediamine according to the procedureof H. Stetter, Ber. 86, 196- 205 (1953).

PROCEDURE 13 the products of the present invention bearing two differentsulfonamido groups in the benzene ring. For instance,3-(p-toluenesulfonamido)methanesulfonanilide is obtained in Procedure 13by using p-toluenesulfonyl chloride in the second stage.

The methanesulfonanilides of Procedures 11, 12 and 13 are treated withbromoacetylbromide under the Friedel and Crafts conditions specified inProcedure 10. Procedure 10 is also adapted to the preparation ofcorresponding (Z-bromopropionyl) methanesulfonanilides by substitutionof ot-brornopropionylbromide for bromoactyl bromide in this process.These transformations are summarized in Table II below in which theappropriate methanesulfonanilide starting material, the acid halide, andthe product obtained are tabulated.

TABLE II.REPRESENTATIVE KETONE INTERMEDIATES BY THE FRIEDEL AND CRAFTSMETHOD PROCEDURE 14 3 (2 bromaacetyl)methanesulfonanilide.-Bromine, 60.5g. (0.38 mole), is added dropwise during a period of 2% hrs. to astirred suspension of 81 g. (0.38 mole) of 3-acetylmethanesulfonanilideand 0.8 g. of benzoyl peroxide in 800 ml. of anhydrous ether. Afterstirring overnight, the precipitated product is collected on a filterand washed with ether, yielding 101 g. (91%) of white product, M.P. 121C. One crystallization from isopropanol, 5 ml. per gram of solids,affords 87.5 g. (78.8%) of the product is a white crystalling (plates)solid, M.P. 124.5-126 C.

Analysis.C, 37.30; H, 3.57; Br, 27.06; S, 10.92.

methanesulfonyl chloride in pyridine solution by the 7 method ofProcedure 1. The intermediate amino-acetophenones and resultingmethanesulfonanilides are arranged in the table in columns parallelingthe acetophenones.

TAB LE III.-2-SUB STITUTED--(ACETYL)METHANESUL- FONANILIDES MR StartingAminoacetophenone Methanesulfonanilide Acetophesone 4-bromoaeetophenone.3-amino-4-bromo- 2-bromo-5-acetylacetophenone. methsnesulfonanilide. 4iodoacetophenoneuh 3-amino-4iodoaceto- 2-iodo- -acetyl-methphenone.anesultonanilide. 4fluoroacetophenone 3-amino-4-fiuoro-2-fiuoro-5-acetylmethacetophenone. anesulfonanilide. 4-methylacetophe-3-amino4-methyl- 2-methyl-5-acetylnone. acetophenone. metlaanesulfonam 1e.

TABLE IV.BROMOAOETYLSULFONANILIDE INTE RMEDIATE S AcetylsulionanilidesBromoacetylsulfonanilides 3-(acety1) ethanesulionanilide3-(acety1)bntancsulfonanilide 3-(acetyl)benzenesulfonanilide3-(2-bro1noacetyl) ethanesulfonanilide. 3-(2-bro1noacetyl)butanesulfonanilide. 3-(2-blrgmoacetybbenzenesulfonam3-(acetyl)-p-toluenesulfonanilide 3-(2-li 1r()ln10acetyl)-4-tolnenesultonan 1 e 3-(propionyl)methanesulfonanilide.

2-chloro-4-(acetyDmethanesulfonanilide.

3-(2-bro1nopropionyDmethanesulfona 'lide.

2-chloro-4-(Z-bmmoacetyDmethanesulionanilide.

5-acetyl-2-benzyloxymethane- 5(2-bromoacetyl)-2-benzyloxysulfonanilide.methanesulfonanilide. 5-propionyl-2-benzyloxymethane-5-(Z-bromopropionyl)-2-benzylsulfonanilide. oxymethanesulfonanilide.2-chloro-5-(acetyDmethanesulfon- 2-chloro-5-(2-bromoacetyl)methnilideanesulfonanilide.

a 2-bromo-5-(acetyDmethanesull'on-2-broIno-5-(2-brom0acetyl)methanilide. anesulfonanilide.

2-iodo-5-(2-bromoacetyl)methanesulfonanilide.2-fluoro-5-(2-bromoacetyl)methanesulfonanilide.2methyl5-(2-br0moacetyl)methanesulfonanilide.5-(2-bromoacetyl)-2-methoxy- Inethanesulfonanilide.

2-iodo-5-(aeety1)methanesulfonanilide.

2-fluoro-5-(acetyl)methanesulfonanilide.

2methyl-5-(aeetyDmethanesulfonanilide.

5-acetyl-2-methoxymethanesulfonanilide.

2-chloroacetyl sulfonanilides, 2-chloropropiony1 sulfonanilides,2-iodoacetyl sulfonanilides, and 2-iodopropionyl sulfonanilides ofFormula II corresponding to the products of Procedures and 14 and theproducts listed in Tables II and IV may be prepared by application ofknown methods to the appropriate starting materials. For example,substitution of chlorine for bromine in Procedure 14 provides the2-chloroacyl sulfonanilides. The method of A. Lucas (Ber. 32, 601(1899)) for the preparation of 2-iodoacetophenone by the action ofalcoholic potassium iodide on 2-bromoacetophenne is readily applicableto the substituted 2-bromoacetophenones and 2- bromopropiophenones ofProcedures 10 and 14 and Tables II and IV to provide the correspondingiodo compounds. The resulting 2-iodoacyl intermediates are moreconvenient for reaction with amines as is described hereinafter in someinstances due to the enhanced reactivity of the iodine atom. On theother hand the 2-chloroacyl intermediates are sometimes preferable forcommercial production due to the relatively low cost of chlorine. Thebromine compounds are generally convenient for laboratory studies.

PROCEDURE 15 3 (2 benzylmethylaminoacetyl)methanesulfonanilidemethanesulf0nate.-A solution of N-benzylmethylamine, 7.27 g. (0.06mole), in 25 ml. of acetonitrile is added dropwise during 10 min. to asolution of 8.76 l (0.03 mole) of 3-(2-brornoacetyl)methanesulfonanilidehaving M.P. 118121 C. in ml. of acetonitrile. EX- ternal cooling isemployed to maintain a reaction temperature of 10 C. during theaddition. The cooling bath is then removed and the solution stirred foran additional 20 min. Concentration of the reaction mixture yields ayellow oil which is dissolved in 300 ml. of ether and washed with waterto remove by-product N -benzylmethyl amine hydrobromide.

The ethereal solution is dried over magnesium sulfate and the solventdistilled leaving a viscous oil. The oil is purified by dissolving inether (250 ml.), and filtering the ether solution through diatomaceousearth to remove insoluble colored impurities. The treated ether solutionis diluted with 100 ml. of acetonitrile. Treatment of theether-acetonitrile solution with an ether solution of methanesulfonicacid yields 3-(2-benzylmethylaminoacetyl) methanesulfonanilidemethanesulfonate as a white precipitate which is collected and washedwith 100 ml. of 1:1 acetonitrile-ether and dried. It weighs 9.0 g.(70%), and exhibits M.P. 197.5-201 C. It is recrystallized from 96%ethanol, yielding 8.0 g. (62.3%) of the pure crystalline product, M.P.206209 C.

Analysis.C, 50.70; H, 5.75; S, 14.85. Infrared absorption maxima (0.5%in KBr pellet): 2.98, 3.37, 5.95, 6.25, 6.35, 6.84, 7.05, 7.15, 7.55,8.00, 8.30, 8.55, 8.73, 8.96, 9.61, 10.03, 10.31, 10.90, 12.87, 13.42,and 14.3 4.

PROCEDURE 16 3 (2 methylamino 1 hydr0xyethyl)m-ethanesulfonaniliaemethanesulf0naze.A solution of 31.8 g. (0.74 mole) of3-(2-benzylmethylaminoacetyl)methanesulfonanilide methanesulfonate in700 ml. of absolute ethanol is reduced in an atmospheric hydrogenationunit (2 to 5 p.s.i.g. positive pressure) during twenty-four hours with a10% palladium catalyst prepared from 320 mg. of palladium chloride and2.0 g. of pulverized charcoal. After absorption of the calculated amountof hydrogen, the catalyst is filtered, the filtrate concentrated toabout 100- ml., mixed with about 500 ml. of ether, resulting inprecipitation of a white solid weighing 24.3 g. (96%), M.P. 201203.5 C.Two recrystallizations from ethanol (35 mL/g. of solid) yield theanalytically pure product, 19.6 g. (75%), M.P. 207-209 C.

Analysis.C, 39.08; H, 5.92; N, 8.11; S, 18.60. Infrared absorptionmaxima (0.5% in KBr): 3.02, 3.22, 6.23, 6.81, 7.09, 7.44, 7.81, 8.30,8.63, 9.07, 9.31, 9.52, 10.12, 10.35, 10.52, 10.90, 11.11, 11.73, 12.29,12.54, 12.93, and 14.11

The method of Procedure 15 is applied to the reaction of the amineslisted in Table V with 3-(2-bromoacetyl) methanesulfonanilide. Theresulting 3 (2 substituted aminoacetyDmethanesulfonanilides are thenhydrogenated to the corresponding 3-(2-substitutedamino-l-hydroxyethyl)methanesulfonanilides according to the method ofProcedure 16. The aminoacetyl intermediates and the aminoethanol endproducts are also listed in Table V.

TABLE V.-3-SUBSTITUTED METHAN Amine Benzylethylamine Benzyl-(1pl1enoxy-2-propyl) amine Pyrrolidine Morpholine PlperidineThiamorpholiue 2-phenylethylamine 4-phenyl-2-butylamine1-(4Jnethoxyphenyl)-2-propylamine1-(3,4-metl1yleuedioxyphenyl)-2-propylamine l-(4-benzy1oxyphenyl)-2p1'opylamine 1- (3-meth oxy-4-benzyloxyphenoxy) -2-propylamine.

anilide as the starting fonanilide methanesulfonate.

ESULFONANILIDES Aminoaeetyl Intermediate 3- (2-begzylethylaminoacetyl)meth auesulfon- 3-[2-(benzyl-(1-pheno1ry-2-propy1)amino) acetylI- methanesulfonanilide.

3- (2pyrrolidinoacetyl)methanesulfonanilide 3-(2-morpholinoacetyl)methanesulfonanilide. 3- (2-p1peridinoacetyl)meth anesultonanilide3-(2-thiamorpholinoaeetyl)methanesulfonanilide.3-[2-(2-phenylethylamino) acetyl1methanesulionanilide 3-[2-(4-phen 1-sulionanilide. 3-[2-(1-(4-methoxyphenyl)-2propylamino)acetyl]methanesultonanilide.3-[2-(1-(3,4-metl1ylenedioxy'phenyl)-2-propylamino)acetyHmethanesuli'onani'de. 3[2-(1-(4-1)enzyloxyphenyl)-2-propylamin0)-acetyflmethauesulfonanilide. 3-[2-(1-(3-metl1oxy-4-benzyloxyphenoxy)-2-propylamino)acetyl1methanesultonanilide.

butylamino) acetyl1methaneaccording to the of Pro 25 Similarly themethods of Procedures 15 and 16 in sequence are applicable to other2-bromoacyl sulfonanilides. of such starting materials, the aminoacetylintermediates, and the aminoethanol Table VI contains an illustrativelist end products obtainable therefrom.

TABLE VI.-OTHER (2l\1EIHYLAMiNO-1-HYDROXYETHYL) Bromoacetyl StartingMaterial 3- tz-bromoacetyl) ethanesultonanilide 3- (2-bromoacetyl) butancsulfonanilide 3- (2-bromo acetyl)benzenesullouanilide 3-(2-bromoacetyl)-p-toluenesultonanilide 5- (2-bromoacetyl)-2-benzyloxymethanesulionanilide.

5- (2-bromopropionyD-2-h enzyloxymethanesultouanilide.

4- (2-brom opropionyl)-p-toluenesulionanil1de 4-(2-bromopropionyl)methancsulionanilide 2-benzyloxy-5-(Z-broruoaeetyl)methnnesulionanilide.

2-nitro4 (2-bron10 acetybmethanesulio nanilide. 2,4-bis-n1ethanesulfonamidophenacyl bromide 2-methyl-5- (2-bromoacetyl)methanesulfonanilide.

4-(Z-bromoacetyl)-2-methoxymethanesulionanllide.

sulionate exhibits M.P. 157159 C.

propanol.

AI'LlllZ/8i8.-C, 56.23; H, 5.63; N, 5.70; S, 13.08. Infrared absorptionmarn'ma in KBI pellet): 2.91, 3.25, 5.88, 6.22, 6.70,

8.25, 8.40, 8.67, 8.90, 9.20, 9.68, 9.90, 10.25, 10.82, 12.27, 2442-11enzylmethylaminopropionyhmethanes Ml. 173.5176.5 C. (dee) afterrecrystallization from ethanol.

62.42; H, 6.82; N, 8.26.1ntrared absorption maxmla (0.5%

Analysis-C,

PROCEDURE 17 4-[2-(1-phenoxy 2 propylamino) 1 hydroxyethyl]methanesulfonanilide hydrochloride-N benzyl-( l-phenXy-2-propyl)amineand 4-(2-bromoacetyl)methanesulstarting materials in Pro- (i.e.4-[2-(benzylnesulfonanilide is h is recrystallized en hydrogenated 75fonanilide are substituted as cedure 15. The product of this reactionl-phenoxy-Z-propylarnino) acetyl1metha recovered as the hydrochloridesalt whic from ethanol-isopropyl ether. It is th utter reery AminoacetylIntermediate 3-(2-benzylmethylaminoacetyl) ethanesulfon- 3- zgllialglzylmethylaminoaeetyl)butanesulion- 3- sibling-31methylaminoacetyl)benzenesulton-3-(2-benzyhnethylaminoacetyD-p-tolueuesulfonamlide.-(2-benzylmethylaminoacetyl)-2-benzyloxymethanesulionanilide.5-(2-benzylmethylaminopropionyl)-2-beuzyloxymethanesulfonanilide.4-(2benzylmethylaminopropionyl)-p-toluenesulfonanilide.4-(2-benzylmethylaminopropionyl)methanesulionanilide.2-benzyloxy-5-(Z-benzyhnethylaminoacetyl) methanesulfonanilide.2-nitro-4-(2benzylmethylaminoaeetybmethauesultouanilicle.3-methanesulionamido-4-(2-benzylmethylamlnoacetyl)methanesultonanilide.2-methyl-5-(2benzylmethylamiuoacetyl)methanesultonaniiido.4-(2-benzylmethylaminoacetyD-hnethoxy- Aminoethanol Product3-(2-ethylamino-l-hydroxyethyl)methane sulfonanilide.3-[2-(1-phenoxy-2propylamino) l-hydroxyethyllmethauesuliona ide. 3(2-yrrolidino-1-hydr0xyethy1)methanesu fonanilide.3-(2-morpholino1hydroxyethyl)methanesulfonauilide.3-(2L3)iperidino-l-hydroxyethyl)methanes ionanilide.3-(2-thiamorpholino-l-hydroxyethyl)methanesulfonanilide.3-[2-(2phenyletliylamino)-1-hydroxyethyl1- methanesulfonanilide.3-[2-(4phenyl-2-buty1amiuo)-1-hydroxyethy1] methanesultouanilide. 3-[2-(1- (4methoxyphenyl) -2-propylamino) -1-hydroxyethyllmethanesulfonanilide. 3-[2-(1-(34ethylenedioxyphenyl)-2-propylamino)-1-hydroxyethyl]methanesultonanilide.3-l2-(1(-4-hydroxyphenyD-Z-propylamino)-1-hydroxyethyl]methanesulfonanilide.3-[2-(1-(3-methoxy-4-hydroxyphenoxy)-2-propylamino)-1-hydroxyethyl]methanesultonanilide.

method of Procedure 16 yielding the H, 6.65; S, 8.81; infraredabpellet): 2.93, 3.03, 3.25, 7.70, 8.02, 8.58, 9.26,

PROCEDURE 18 4-(2 methylaminoacetyl)methanesulfonanilidehydrochloride.-A nearly saturated solution SULFONANILIDES AminoethanolProduct 3-(2-rnethylamino-l-hydroxyethyl)ethanesulionanilide.3-(2-metl1yla1nino-1-l1ydroxyethyl)butanesulionanilide.3-(Z-methylamino-l-hydroxyethyl)benzenesulfonanilide.3-(2-n1ethylamino-l-hydroxyethyl)-p-toluenesulfonanilide.5-(2-methylamino-l-hydroxyethyl)-2-l1ydroxymethanesulionanilide.5-(2-methylarnino-1-l1ydroxypropyl)-2-hydroxymethanesulfonanilide.4-(2-metl1ylaminol-hydroxypropyl)-p-toluenesultonanilide.4-(2-methylamino-1l1ydroxypropybmethnnesulionanilide.2-hydroxy-5-(2-methylamino-1-hydroxyethyl) methanesulfonanilide.2-amino-4-(2-methylamino-l-hydroxyethyl) methanesulfonanilide.3-methanesu1fonamido4-(2-methylamino-1-hydroxyethyl)methanesultonanilide.2-methyl-5-(2-n1ethylamino-l-hydroxycthyl) methanesullonanilide.4'(2-rnethylarnino-1-l1ydroxyethy1)-2-methoxy- 12.93, and 13.60 1.

4-(2-brornoacetyl)methanesulfonanilide, mole) is then added thereto inportions with external cooling of the flask to maintain the temperatureof the contents within the range of -15 C. Methanol, 200 1111., is thenadded to the solution and stirring continued for an additional 10 min.amine is removed in vacuo and the yellow solution remaining is acidifiedwith 175 ml. of 4 N ethanolic hydrochloric acid at 7 34-(2-methylaminohygiroxirpropyl)methanesultonanilidehydrochlomethanesulionanilide. methanesulionauihde. ltonanilidep-toluenein KBrpellet) 3.11, 3.35, 3.40, 3.43, 3.54, 3.61, 5.98, 6.26,6.34, 6.63, 6.71, 6.81 stallization from iso 6 90, 7.05, 7.16, 7 30,7.58, 7.70, 7. 7, 8.12, 8.49, 8.70, 8. 0, 9.13, 9.35, 9.65, 9.76,

9 83, 10 15, 10.28, 10 80, 11.85 12 00, 12.30, 12.90, 13.32, 13.53, and14.50 1.

2.80, 7.04, 7.45, 7.73, 7.95, ride exhibits M1. 21 -218 0. siteecrystallization from ethanol.

13.42, and 14.651. Analysis.-C, 44.63; H, 6.55; Cl, 11.90. ablniraredsorption maxima (0.5%

ulfonanihde exhibits in KBrpellet) 2.98, 3.12, 3.35, 6.2 6.63, 6.89,7.13, 7.32, 7.50, 7.55, 7.85, 7.95,

Substantial excess monomethyl- C. The hydrochloride salt of the deofmonomethylamine in 300 ml. of isopropanol is prepared. Powdered 13 14sired product precipitates and is collected and washed added dropwiseduring 1% hrs. to a stirred mixture of With 200 ml. of 1:1isopropanol-methanol, 300 ml. of 48.8 g. (0.02 mole) of m-nitrophenacylbromide in 500 methanol, and with ether in that order. The Washing ml.of dry acetonitrile at 25-30 C. The reaction mixture procedure isnecessary to remove by-product monomethylis stirred for an additional 4hrs. at room temperature.

amine hydrobromide; product yield is 37.0 g., M.P. 5 PrecipitatedN-benzylisopropylamine hydrobromide is re- 201209 C. (dec.). Thismaterial is recrystallized from moved by filtration, and the filtrateconcentrated in vacuo. 1:2 Water-isopropanol, M.P. 240242 C. (dec.). Theresidue is dissolved in 800 ml. of ether, and washed Analysis.Cl, 12.67;N, 9.85; S, 11.38. Maximum ab- With three 150 ml. portions of Water. Theether solution sorption in the infrared region (0.5% in KBr pellet): isdried over MgSO and diluted to about 1600 ml. with 2.95, 3.28, 3.33,3.45, 3.60, 5.97, 6.26, 6.63, 6.81, 7.15, ether. It is then mixed withabout 1 equivalent of 4 N 7.33, 7.52, 7.68, 8.08, 8.42, 8.70, 9.48,9.81, 9.94, 10.28, ethanolic hydrogen chloride to precipitate thedesired 10.67, 11.13, 11.78, 12.28, 12.83, and 14.10,. hydrochloridesalt as a yellow oil which solidifies on standing; Weight 59 g. (84.7%),M.P. 140-155 C. PROCEDURES 19 21 (dec.). It is recrystallized severaltimes from 1:1:2 By substitution of the amines listed in Table VII in [5tha ol-a eto e-i o ro yl ether, M.P 161-163 C. (deq), the process ofProcedure 18, the products listed therein are obtained. A Weight ofamine 10% in excess of the PROCEDURE 27 stoichiometric amount is used inthese examples. The re- 2 b'enzylz'sopropylamino 3 aminoacetophononaaction solvent, and recrystallization solvent, is listed for2-benzylisopropylamino 3' nitroacetophenone hydroeach example, and themelting point, the analysis, and chloride, 20.9 g. (0.06 mole) is addedin one portion to infrared absorption maxima for each product. a stirredsolution of 36 g. of stannous chloride dihydrate TABLE VII.-ADDITIONALAMINOACEIYL METHANESULFONANILIDES Procedure Amine Product ReactionCrystallization Melting Point Analysis Infrared N Solvent Solvent Maxima1 19 lsopropylamine. 4(2-isopropylaminoacetyl) Methanol-.. Methanol217219 O. (dec.) 01, 11.62 (a) methanesulfonamlide hydro- N, 8. 87chloride. S, 10. 63 20 Diethy1amine 4-(2-diethylaminoacetyl) Benzene".-.13:5 methanol- 213-215 C. (dee.) C1, 11.13 (b) methanesulfonanilidehydroisopropyl ether. N, 8. 56 chloride. S, 9. 65 21 Dibenzyla-4-(2-dibenzylaminoacetyl) Aeetone. Ethanol 199.5201.5 C. (dec.) 0, 62.29 (c) mine. methanesulionanilide hydro- H, 5. 71 chloride. 01, 7. 92 N,6. 40 S, 7.27 Infrared absorption maxima (0.5% in KBr pellet): (b) 2.94,3.35, 3.43, 3.51, 3.63, 5.95, 6.23, 6.60, 6.72, 6.80, 7.07, 7.31, (a)2.95, 3.24, 3.39, 3.57, 3.70, 3.93, 4.15, 5.96, 6.25, 6.62, 6.82, 7.08,7.50, 7.67, 7.80, 7.92, 8.08, 8.42, 8.68, 9.40, 9.52, 9.88, 10.10,10.35,

7.17, 7.24, 7.33, 7.55, 8.11, 8.42, 8.70, 9.40, 10.13, 10.30, 10.95,11.50, 10.9 11.90, 12.23, and 13.00;. 1102,1208, and 12.63 1. (0) 2.93,3.31, 3.43, 5.91, 6.24, 6.60, 6.84, 7.10, 7.45, 7.65, 7.85, 8.41,

8.68, .21, .10,10.30,10.97,11.92,12.22,13.30,and14. ,1.

PROCEDURES 2225 in 60 ml. of concentrated hydrochloric acid While main-The method of Procedure 16 is applied to the aminotlining a reactiontfimperamre 40-450 with Occa acyl methanesulfonanilides of Procedures1821. The re- 510ml external coohng' An addmonal 35 of concen sults aresummarized in Table VIII in Which the trated hydrochloric acid is addedand stirring continued cedure number, name of the product, meltingpoint, ref r /2 hr., and the mixture then kept at room temperaturecrystallization solvent, and analysis are given. for 1 hr. The mixtureis then added to an aqueous TABLE VIII.ADDITIONAL AMINOETHANOLMETHANESULFONANILIDES Procedure Product Melting Point RecrystallizationSolvent Analysis Infrared N o. Maxima 2 22 4-(2methylamino-l-hydroxyethyl) meth- 181-183 C 5:1 ethanoLether C, 42. 90(a) anesulionanilide hydrochloride. H, 6. 09 Cl, 12. 51 9.70 S, 11.38 234-(2-isopropylamino-l-hydroxyethyl) 2025-203" 0. (dee) :1ethanol-methanol Cl, 11. 51 (b) methanesulfonanilide hydrochloride. N,8. 96 S, 10.30 24 4-(2-diethylamino-1-hydroxyethyl)meth- 86.5-88.5 0Isopropyl ether N, 9.59 (c) anesulfonauilide. 1 S, 11. 02 254-(2-benzylamino-1-hydr0xyethyl) meth- 202.5203.5 C. (dee) Ethanol. C,54. 09 (d) anesulionanilide hydrochloride. H, 6. 02 Cl, 9.84 N, 7. 1 Thecrude hydrochloride is converted to the free base by treatment (b) 2.93,3.23, 3 36, 3.52, 6.20, 6.30, 6.61, 6.87, 7.19, 7.53, 8.16, 8 31, withmethanolie sodium methoxide and purified and analyzed as the free 8.64,9.31, 9.60, 9 3, 10.16, 11.08, 11.60, 12.00, and 1290;. base. (0) 2. 5,3. 340, 350, 3.85, 6.22, 6.63, 6.85, 7.23, 7.55, 7.81, 8.08, 2 Infraredabsorption maxima (0.5% in KBr pellet): 8.20, 8.34, 8 67, 948, 9.80,1032, 11.00, 11.21, 11.80, 12.89, and

8.18, 8. 8.63, 9.04, 9.28, 9.65, 9.83, 10.20, 10.43, 10.97, 11.60,11.85, (d) 2.91, 3.08, 3.15, 3.40, 3.55, 6.20, 6.58, 6.82, 7.13, 7.51,8.15, 8.65, 12.15, 12.40, 12. 011. 9.27, 9.82, 10.30, 10.90, 11.28,11.95, 13.30, and 14.2

PROCEDURE 26 2 benzylisopropylamina-3'-nitroacetop2zenone hydro- Ayellow sticky precipitate forms which 18 recovered bychloride.N-benzylisopropylamine, 59.7 g. (0.4 mole) is extraction into300 ml. of chloroform and the solution 15 dried. Evaporation of thesolvent leaves a yellow residue which solidifies on trituration withanhydrous ether, M.P. 8690 C., wt. 9.2 g.

PROCEDURE 28 3-(2-benzylisopropylaminoacetyl) methanesulfonanilidemethanesulfonate.-A solution of 5.65 g. (0.0325 mole) of methanesulfonicanhydride in 50 ml. of chloroform is added to a stirred solution of 9.17g. (0.0325 mole) of 2-benzylisopropylamino-3'-aminoacetophenone in 125ml. of chloroform. An exothermic reaction occurs. External cooling isemployed to keep the temperature below 20 C. The yellow solution is thenkept overnight and then concentrated in vacuo. The gummy residue iswashed several times with ether and then dissolved in 75 ml. of warmethanol. The desired product crystallizes from the solution on cooling.It is collected, washed on the filter with 25 ml. of cold absoluteethanol, and dried, weight 13.3 g. (90%), M.P. 170-175 C. It isrecrystallized from 3:1 ethanol-isopropyl ether for analysis, M.P.178.5181 C. (dec.).

Analysis-C, 52.77; H, 6.26; S, 13.88. Infrared absorption maxima areexhibited at the following wave lengths (0.5% in KBr pellet): 2.95,3.35, 5.94, 6.25, 6.37, 6.83, 7.13, 7.50, 7.55, 7.76, 7.99, 8.25, 8.41,8.68, 9.59, 10.02, 10.25, 10.85, 11.35, 12.60, 12.80, 13.05, and 1425p.

PROCEDURE 29 3 (2 isopropylamino-Z-hydroxyethyl)methmzesulfonanilidemethanesuIf0nate.-Procedure 16 is repeated, substituting 3-(2benzylisopropylaminoacetyl)methanesulfonanilide methanesulfonate as thestarting material. The product is recrystallized from 2:1 ethanol-ether,M.P. 146-148 C. with softening at l43.5 C.

Analysis.C, 42.56; H, 6.54; S, 17.33. Significant absorption maxima inthe infrared region of the spectrum are exhibited at the following wavelengths (0.5% in KBr pellet): 2.90, 3.35, 6.24, 6.30, 6.80, 7.15, 7.58,8.37, 8.70, 9.10, 9.35, 9.57, 10.00, 10.20, 12.85, and 14.20 1.

PROCEDURE 30 4 (2 aminoacetyl)methanesulfonanilide hydrochloride.--Amixture of 29.2 g. of 4-(2-bromoacetyl)methanesulfonanilide and 21 g. ofhexamethylenetetramine in 1250 ml. of chloroform is refluxed withstirring for 3 hrs. The mixture is then filtered while still hot and thecake washed with fresh chloroform and then triturated with hot acetone.The desired intermediate,4-(2-hexamethylenetetramoniumacetyl)methanesulfonanilide bromide,remains as a white acetone-insoluble solid weighing 42.0 g. Thismaterial is then suspended in 1 1. of ethanol containing 50 ml. ofconcentrated hydrochloric acid and refluxed for 5 min. The hot solutionis then treated with decolorizing carbon, filtered, and allowed to cool.4-(2- aminoacetyl)rnethanesulfonanilide hydrochloride separates as awhite crystalline precipitate which is collected, washed, and dried,weight 29.5 g. A further amount is obtained by concentration of thefiltrate to 150 ml. and mixing with 300 ml. of diethyl ether, weight 9.0g. The combined portions are then recrystallized several times fromethanol containing hydrochloric acid. The material melts withdecomposition when heated in a capillary tube but it is difficult to geta reproducible melting point; M.P. 240.5-243" C. (dec.) is observed whenusing a preheated bath.

Analysis.-Cl, 13.26; N, 10.26; S, 12.28. Infrared absorption maximaoccur at (mineral oil suspension): 2.82, 2.97, 3.11, 5.91, 6.22, 6.62,7.50, 7.64, 7.91, 8.08, 8.43, 8.72, 9.02, 10.20, 10.27, 10.37, 10.45,10.85, 12.11, 13.20, and 13.82;!

PROCEDURE 31 3 (2 aminoacetyl)methanesulfonanilide hydrochloride.-Theprocess of Procedure 30 is repeated, substituting3-(2-bromoacetyl)methanesulfonanilide as the starting material inreaction with hexamethylenetetramine. The

16 1 intermediate hexamethylenetetramonium salt is decomposed in thesame fashion to provide the desired product which is recrystallizedfirst from ethanol containing hydrochloric acid and finally from ethanolto provide the purified material, M.P. 200-201.5 C. (dec.).

Analysis.-C, 40.68; H, 4.70; Cl, 13.68; N. 10.29.

PROCEDURE 32 crude material exhibits no carbonyl absorption in theinfrared region of the spectrum, an indication that the reduction hasbeen satisfactorily completed. The product is recrystallized from about75 ml. of absolute ethanol containing 35 drops of water, weight 4.2 g.,M.P. 188- 189.5 C. (dec.).

Analysis.-C, 13.30; infrared absorption maxima (0.5% in KBr pellet):3.03, 7.51, 7.70, 8.16, 8.28, 8.62, 12.60, and 13.35 1.

N, 10.16. The product exhibits at the following wave lengths 3.33, 6.25,6.60, 6.77, 7.10,

PROCEDURE 33 3 (2 amino 1 hydroxyethyl)methanesulfonanilidehydr0chl0ride.-The procedure of Procedure 32 is repeated substituting3-(2-aminoacetyl)methanesulfonanilide hydrochloride as the startingmaterial. The product is a. white crystalline solid which is purified byrecrystallization from ethanol-ether, M.P. 161.5 C.

Analysis.--C, 40.63; H, 5.53; Cl, 12.99; N, 10.73. Infrared absorptionmaxima are observed at (0.5% in KBr pellet): 2.91, 3.15, 3.19, 3.25,3.35, 3.58, 3.70, 3.81, 6.18, 6.52, 6.70, 6.92, 7.02, 7.16, 7.40, 7.55,7.85, 7.95, 8.65, 9.05, 9.46, 9.85, 10.15, 10.30, 10.88, 11.10, 11.27,11.57, 12.70, 13.22, and 1424p.

PROCEDURE 34 3 (2 methylamz'no 1 hydroxyethyl)methanesulf0nanilicie.-3(2 methylamino 1 hydroxyethyl) methanesulfonanilide methanesulfonate(from Procedure 16), 17.0 g. (0.05 mole), is dissolved in 50 ml. of 1 Nsodium hydroxide, yielding a yellow solution having pH 8.

The water is removed from the solution by evaporation in vacuo and theresidue is treated with several portions of ethanol which are evaporatedto remove last traces of moisture. The bulk of the sodiummethanesulfonate byproduct is then removed from the residue bydissolving the product in 350 ml. of hot absolute ethanol and clarifyingby filtration through a diatomaceous earth filter aid. The ethanolicfiltrate is evaporated to dryness. Last traces of sodiummethanesulfonate are then removed by washing the residue with 15 ml. ofcold water and then with two 15 ml. portions of 1:1 coldwater-isopropanol, and finally with ether, yielding 7.7 g. of whitesolid, M.P. 159- 161 C. Treatment of a small portion of this materialwith methane sulfonic acid in absolute ethanol yields themethanesulfonate salt identical with the starting material of thisprocess, indicating that no structural. alteration of themethanesulfonanilide had occurred. during preparation of the amphotericform thereof, also referred to herein as the free base form.

Analysis.C, 49.06; H, 6.52; N, 11.28; S, 13.11. Infrared absorptionmaxima are exhibited at the following wave lengths (0.5 3.47, 3.55,6.20, 6.75, 6.74, 7.10, 7.52, 7.70, 8.18, 8.50, 8.73, 9.00,'9.44, 9.90,10.10, 10.34, 10.88, 11.45, 12.65, and 1428 in KBr pellet): 2.93, 3.04,3.20, r

1 7 PROCEDURE 3s 3 (2 methylamino-I-hydroxyethyl)methanesulfonanilidehydrochlride.3 (2 methylamino-l-hydroxyethyl)methanesulfonanilideprepared as described in Procedure 34, 2.44 g., is suspended in 35 ml.of boiling isopropanol and the suspension acidified with approximately 4molecular proportions of ethanolic hydrogen chloride. The suspended freebase promptly dissolves and the desired hydrochloride salt deposits as awhite crystalline solid on cooling, weight 2.6 g., M.P. 148151 C. Thismaterial is recrystallized from a combination of 25 ml. of isopropanoland ml. of ethanol, yielding 2.4 g. of the purified white crystallinehydrochloride salt, M.P. 154-155.5 C.

Analysis-C, 43.02; H, 6.37; CI, 12.55; N, 10.14; Infrared absorptionmaxima (0.5% in KBr pellet): 3.00, 3.20, 3.31, 3.55, 4.10, 6.20, 6.75,7.12, 7.49, 8.65, 9.30, 9.68, 9.95, 10.20, 10.84, 11.43, 12.63, 12.90,and 14.20

Substitution of the following acids for hydrogen chlo ride in Procedure35 provides other acid addition salts illustrative of those within thescope of the present invention: hydrogen bromide, acetic acid, propionicacid, phosphoric acid, nitric acid, succinic acid, gluconic acid,

removed and the reaction mixture is stirred for min. at roomtemperature. It is then concentrated to a syrupy mass in vacuo, ml. ofanhydrous ethanol is added to the residue, and the solvent againdistilled leaving a white solid residue. This material is partiallydissolved in 25 ml. of methanol, insoluble material removed byfiltration, and the filtrate acidified with ethanolic hydrochloric acid,resulting in formation of a solution of the desired product containing asmall amount of insoluble material. The latter is removed 'byfiltration, the filtrate concentrated to dryness, and the residuetriturated with 15 ml. of isopropyl alcohol. The product weighing 2.5 g.is recovered from the isopropyl alcohol suspension by filtration, M.P.195198 C. It is recrystallized from a mixture of methanol and ethanol toprovide the desired substance, M.P. 201.5202.5 C. (dec.), which isidentical in every respect with the product produced above in Procedure23.

The nuclearly substituted phenacyl halides listed in Table IX areallowed to react with methylamine under the conditions of Procedure 18and the resulting Z-methylaminoacetylrnethanesulfonanilides are reducedwith sodium borohydride according to Procedure 37. The intermediatemethylaminoacetylmethanesulfonanilides and the resulting reductionproducts are also listed in Table IX.

TABLE IX.HALOGENATED AND BENZYLOXY SULFONANILIDES Phenacyl HalidesIntermediates Products 2-chloro-5 (2-bromoacetyl) methanesulfonam'lide.2-br0mo-5-(2bror.noacetyl) methanesulfonanilida. 2-fiuoro-5-(2-bromoacetyl) methanesullonanilide.

2iodo-5-(Z-bromoacetyl)methanesulfonanilide. 2-ch1oro-4- (Z-bromoacetyl)methanesulfonanilide.

fonauilide.

fonanilide.

fonamhd fonamlide.

fonanihde.

2-benzy1oxy5-(2-bromoacetyl) methanesulfonanilide. sulfouanilide.

2-ch101'0-5-(Z-methylarnino-l-hydroxyethyl)- methanesulfonanilide.2-bromo-5-(2-methylamino-l-hydroxyethyl)- methanesulfonanilide.2-fluoro-5-(Z-methylamjno-l-hydroxyethyl)- methanesulfonauilide.2-iodo-5-(Z-methylamino-l-hydroxyethyl)- methanesulfonanilide.2-chloro-4-(Z-methylamino-1-hydroxyethyl)- methanesulfonanilide.2-benzyloxy-5(Z-methylaminoJ-hydroxyethyDmethauesulfonanilide.

mucic acid, sulfuric acid, ethanesulfonic acid, p-toluenesulfonic acid,pamoic acid, sulfosuccinic acid, etc.

PROCEDURE 36 3 (2 methylamino-I-hydroxyethyl)methanesulfonanilide sodiumsalt.A lint-free solution of 0.23 g. (0.01 mole) of sodium in about 12ml. of methanol is mixed with a solution of 2.44 g. (0.01 mole) of3-(2-methylamino-1-hydroxyethyl)methanesulfonanilidein 125 ml. ofmethanol. An equal volume of anhydrous ether is then added to themethanolic solution resulting in the immediate formation of a whiteprecipitate. The precipitate is collected, washed with 50 ml. of 1:1methanol-anhydrous ether, and then with ether, yielding the desiredsodium salt as a White crystalline solid, M.P. 249-251 C. (dec.).

Analysis.C, 45.34; H, 5.97; N, 10.41; Na, 8.40.

Substitution of appropriate bases such as the following for sodiummethoxide in Procedure 36 provides the corresponding metal salts:potassium t-butoxide, lithium methoxide, aluminum isopropoxide, etc.Double decomposition processes in which a sodium salt such as thatdescribed in Procedure 36 is allowed to react with a metal salt such asmagnesium chloride, calcium chloride, barium chloride, or zinc chloridein an appropriate solvent allowing either for precipitation of thedesired salt or precipitation of by-product sodium chloride withretention of the desired salt in solution are also suitable.

PROCEDURE 37 4 (2 isopropylamino-I-hydroayet/zyl) m'ethanesulfonanilidehydrochloride by sodium borohydride reduction. Sodium borohydride, 0.38g. 0.01 mole) is added in portions during 10 min. to a solution of4-(2-isopropylaminoacetyl)methanesulfonanilide hydrochloride (Procedure19) in 40 ml. of methanol and 10 ml. of 2 N sodium hydroxide (0.02 mole)at 15-20" C. The cooling bath is present invention having alkoxy groupsattached to the benzene ring such as ethoxy, propoxy, isopropoxy,n-butoxy, sec.butoxy, isobutoxy, or t-butoxy are prepared by alkylationof the phenolic hydroxyl group of intermediates such as4hydroxy-3-nitroacetophenone, or 4-hydroxy-3-nitropropiophenone withalkyl halides or sulfates including n-butyl iodide, sec.- butyl iodide,ethyl iodide, isopropyl bromide, and diethyl sulfate under theconditions of Procedure 4. The resulting alkoxy nitroacetophenones arethen converted to the desired Sulfonanilides as described herein. Othermethods will be apparent to those skilled in the art.

The substances listed in Table X, for example, are prepared from4-hydroxy-3-nitroacetophenone (Procedure 2) by adaptation of Procedure 4to the appropriate alkyl halide and transformation of the resultingproduct according to Procedures 6, 8, 14, 15, and 16.

TABLE X.ALKOXY SUBSTITUTED SULFONANILIDES Sulfonanilides of theS-(Z-methylamino-l-hydroxyethyl) -2- (n-butoxy)methanesulfonanilide 5-(Z-methylamino-1-hydroxyethyl)-2-( sec.-but0xy)rnethanesulfonanilide 52-methylamino-1 -hydroxyethyl) -2- (ethoxy)methanesulfonanilide5-(2-n1ethylamino-1-hydroxyethyl)-2-(isopropoxy)methanesulfonanilidePROCEDURE 3s Nose drops-A solution having a concentration of 0.25% of3-(Z-methylamino-l-hydroxyethyl)methanesulfonanilide methanesulfonate isprepared by dissolving the following ingredients in sufiicient distilledWater to provide 1 1. of solution.

19 3 (2-methylamino-l-hydroxyethyl) methanesul fonanilide, g 2.5Neomycin sulfate, U.S.P., g. 1.10 Sorbitol solution, N.F., ml. 50.0

Methyl parabens, g. 0.40 Propyl parabens, g. 0.20

Sodium citrate, U.S.P., g. 4.40 Sodium bisulfite, A.R., g. 1.00 Aromaticconcentrate, g. 1.00

Other solutions for nasal instillation having concentrations from 0.1 to0.5% may be prepared in this fashion by varying the amount of3-(2-methylamino-1-hydroxyethyl)methanesulfonanilide methanesulfonate.The neomycin sulfate may be omitted if desired, but in such instances itis advantageous to include an additional preservative such as 0.002%w./v. of thimerosal.

PROCEDURE 39 3 (2 methylamino l hydroxyethyl)methanesulfonanilide 5.Magnesium stearate 1.30

The total weight of this preparation is 135 g. It is compressed intotablets, each containing mg. of3-(2methylamino-l-hydroxyethyl)methanesulfonanilide using a standardconcave punch and dye. The batch provides 1000 tablets.

PROCEDURE 4O 4-(2-bromoacetyl)-4-toluenesulfonanilide.-The method ofProcedure 1 is repeated, substituting p-toluenesulfonyl chloride and4-aminoacetophenone as starting materials. At conclusion of the reactionperiod, the mixture is heated to 80 C. and poured into water containingcrushed ice. 4-(acetyl)-p-toluenesulfonanilide precipitates and iscollected on a filter and recrystallized from ethanol, M.P. l99-200 C.This material is then brominated according to Procedure 14. Thebrominated product is recrystallized from acetonitrile, M.P. 174-176 C.(dec.).

Analysis.--C, 49.17; H, 4.05; Br, 20.94; S, 8.78.

This substance is condensed with the amines listed in Table V accordingto the methods of Procedures 15 and 16 to provide a series of4-(2-substituted amino-l-hydroxyethyl)-4-toluenesulfonanilidescorresponding to the aminoethanol products listed in Table V.

Compounds as defined for Formula I wherein R and R are hydrogen and X isother than amino may be employed in reductive alkylation processes tointroduce R substituents of the character specified. This method isillustrated by the following formulas in which R -COR' is an aldehyde orketone related in structure to the R substituent it is desired tointroduce, the carbonyl carbon of R -CO-R corresponding to the carbonatom of R to which the nitrogen atom is attached. For instance, if

is to be 1-phenoxy-2-propylamino, phenoxyacetone is employed asalkylating agent. Various compounds bearing nuclear substituents of thecharacter referred to above for 20 X as well as the simpler typesillustrated in the following equation can be made by this method.

IITHSOzR IIIHSOzRr This procedure is conducted in the usual wayemploying an excess of carbonyl reactant relative to amine reactant, asolvent which is hydrogenation-stable such as acetic acid or ethanol,and catalytic hydrogenation conditions employing preferably a platinum.or nickel catalyst and pressures in the range of from 1-100 atmospheresof hydrogen.

PROCEDURE 41 2 (Z-isopropylamino-I-hydr0xyethyl)methanesulfonanilidehydrochloride.-2-(Z-amino-l-hydroxyethyl)methanesulfonanilidehydrochloride (Table XI, Entry No. 51), 5.0 g. (0.0195 mole), isdissolved in ml. of absolute ethanol and treated with 6.73 ml. of 2.9 Nsodium hydroxide. The precipitated sodium chloride is removed by filtration and 3.4 g. (0.0585 unole) acetone is added to the solution which isthen subjected .to catalytic hydrogenation employing platinum oxidecatalyst, room tempera- .ture, and a pressure of approximately 2 atm.The calculated quantity of hydrogen is absorbed within about 1 hr. andthe product is then isolated by separation of the catalyst by filtrationand distillation of the solvent in vacuo. The residue is dissolved inabsolute ethanol and acidified with ethanolic hydrogen chlorideresulting in formation of the hylrochloride salt of the desired productwhich precipitates on dilution of the solution with anhydrous ether. Thematerial is recrystallized from aqueous ethanol, M.P. 224.5-225.5 C.(dec.).

Analysis.--C, 46.36; H, 6.72;Cl, 11.53; infrared absorption maxima (0.5%in KBr): 3.06, 3.28, 3.41, 3.58, 6.30, 6.72, 6.84, 7.16, 7.50, 7.58,7.77, 8.21, 8.69, 9.01, 9.34, and'l0.30 i.

PROCEDURE 42 3-benzyl0xy-4-nitr0acetophen0ne.-A mixture of 4.25

g. (0.174 mole) of magnesium, 4.0 ml. of absolute ethanol.

and 0.4 ml. of carbon tetrachloride is heated on a steam bath forseveral minutes. To this mixture is added ml. of anhydrous etherfollowed by a solution of 27.8 g. (0.174 mole) of diethyl malonate in 16ml. of absolute ethanol and 20 ml. of anhydrous ether at such a rate asto maintain vigorous refluxing. The mixture is refluxed an additional 3hrs. and then a suspension of 46.0 g. (0.158 mole) of3-benzyloxy-4-nitrobenzoyl chloride, M.P. 101- 104 C. prepared bytreatment of 3-benzyloxy-4-nitrobenzoic acid with P01 in 950 ml. ofanhydrous ether is added portionwise within 30 min.3-benzyloxy-4-nitrobenzoic acid, M.P. 212-214 C., required in thepreceding, may be prepared by treatment :of methyl 3-hydroxy-4-nitrobenzoate with benzyl chloride substantially as de-.

scribed in Procedure 4. .The precipitated green waxy solid graduallychanges to a white suspension after the reaction mixture is refluxed for3 hrs. A solution of 20 ml. of concentrated sulfuric acid in ml. ofwater is then added to the cooled mixture. The aqueous layer isseparated and extracted with ether and the combined ethereal solutionsare washed with water and dried over anhydrous magnesium sulfate. Theother is removed by distillation at reduced pressure leaving 73.0 g. ofa yellow oil. To this oil there is added 47.5 ml. of glacial aceticacid, 6.3 ml. of concentrated sulfuric acid, and 32 ml. of water and themixture is refluxed for 7 hrs. The cooled mixture is ad- 21 justed to analkaline pH with 175 ml. of 20% aqueous sodium hydroxide solution andextracted with ether. The ethereal extracts are washed with water anddried over anhydrous magnesium sulfate. The ether is removed bydistillation at reduced pressure, leaving 47.0 g. of a yellow oil whichsolidifies on standing. Recrystallization of the resulting wax-likesolid from methanol yields 23.5 g. (55%) of material, M.P. 7492 C. Thematerial is purified by dissolving in 200 11111. of ethyl acetate andtreatment with 100 g. of adsorption alumina. The product is recovered byfiltration, distillation of the solvent, and recrystallization fromisopropyl ether; 18.5 g., M.P. 92- 102" C.

PROCEDURE 43 4-amin0-3benzyloxyacetophenone.A mixture of 35.0 g. (0.13mole) of 3-benzyloxy-4-nitroacetophenone is dissolved in 600 ml. ofabsolute ethanol with stirring and heating. The heat source is removedand 3 teaspoonfuls of Raney nickel catalyst suspension, and a solutionof 19.4 g. (0.39 mole) of hydrazine hydrate (99-l00%) in 15 ml. ofethanol is added, the latter dropwise. The mixture is refluxed for 1 hr.and stirred at room temperature for an additional hour. The catalyst isremoved by filtration and the filtrate concentrated by distillation atreduced pressure. The residue is triturated with cold isopropyl etherand the crystalline product filtered; 28.8 g., M.P. 70-76" C. Afterrecrystallization from isopropyl alcohol the material melts at 79-81 C.

Procedures 44 and 45 native method for the Formula I in which Z whichfollow illustrate an alterproduction of those substances of is CHOH andR and R are hydrogen. This method involves nitr-osation of anappropriately ring-substituted acetophenone or propiophenone to providethe 2-oximino ketone which is then reduced to the desiredphenethanolamine or phenpropanolamine.

PROCEDURE 44 2 benzyloxy-S-(2-0ximin0pr0pionyl)methanesulfonanilide.2-bemyloxy-.5-propionylmethanesulfonanilide(10.0 g., 0.03 mole) and 4 ml. of 6.9 N ethanolic hydrogen chloride aremixed in 50 ml. of anhydrous benzene at C. A solution of 4.1 g. (0.035mole) of amyl nitrite in 25 ml. of benzene is added to the mixture andstirring is continued for 2 hrs. at 0 C. The mixture is filtered and theproduct slowly crystallizes from the benzene filtrate. Afterrecrystallization from 2-butanone, the substance exhibits M.P. 150-152C.

PROCEDURE 45 5 Z-amino-J -hydroxypr0pyl -2-hydroxymethanesulfonanilide.Amixture of Z-benzyloxy-S (2-oximinopropionyl)-methanesulfonanilide,palladium-on-carbon, 4 N hydrochloric acid and ethanol is subjected tohydrogenation at 60 p.s.i. and at room temperature until three molecularequivalents of hydrogen have been absorbed. The catalyst is removed byfiltration and the excess hydrochloric acid is neutralized with aqueoussodium hydroxide. The neutralized solution is concentrated to 4 itsvolume by distillation at reduced pressure. An equal volume of water anda fresh charge of 10% palladium-oncarbon catalyst is added to theconcentrate and the resulting mixture is hydrogenated until anadditional molecular equivalent of hydrogen has been absorbed. Thecatalyst is removed by filtration and the product recovered from thefiltrate.

PROCEDURE 46 Ophthalmic solutiom-A buffered, sterile ophthalmic solutioncontaining 0.5% of 3-(2-methylamino-l-hydroxyethyl)methanesulfonanilidemethanesulfonate is prepared from the following ingredients:

3 (2 methylamino-l-hydroxyethyl)methanesulfonanilide methanesulfonate, g5.0 Sodium biphosphate, g 3.20 Sodium phosphate, dibasic, g 0.95

22 Methyl cellulose, 4000 M.C., g. 3.0 Phenylmercuric acetate, g. 0.02

Distilled water, q.s., ml 1000 Ophthalmic solution.-A buttered sterileophthalmic solution containing 5.0% of 3(Z-methylamino-l-hydroxyethyl)methanesulfonanilide methanesulfonate isprepared by the procedure of Example 46 employing 50 g. of activeingredient.

The preceding examples illustrate the preparation of a variety ofcompounds of Formula I in which the Z and NR R functions are joinedthrough but a single carbon atom of the Alk group. Two convenientmethods may be mentioned for the preparation of those substances Wheretwo adjacent carbon atoms of the Alk group form the connesting link.Intermediates of Formula H suitable for this purpose may be formed bythe Friedel-Crafts reaction of a ,B-haloalkanoyl halide such as,B-bromobutyryl bromide on an appropriate sulfonanilide substantially asillustrated in Procedure 10. These intermediates are then transformed byreaction with an amine and reduction of the ketone group to provide aphenpropanolamine in a fashion analogous to preparation of the precedingphenethanolamines.

Another convenient method is the Mannich reaction of a secondary amine,formaldehyde, and a sulfonamido acetophenone such as for example thereaction of dimethylamine, formaldehyde, and3-acetylmethanesulfonanilide illustrated in Procedure 48. The resultingproduct is then reduced to a phenpropanolamine as already described.Conventional Mannich reaction conditions involving mixing the threereactants with or Without a solvent in the presence of an acid at roomtemperature or somewhat elevated temperature, e.g. 30-110 C., aresuitable.

PROCEDURE 48 3 (3 dimethylaminopropionyl)methanesulfonanilidehydrochloride.-A solution of 8.54 g. (0.04 mole) of3-acetylmethanesulfonanilide, 1.6 g. (0.53 mole) of paraformaldehyde,and 4.32 g. (0.53 mole) of dimethylamine. hydrochloride in 10 ml. ofethanol containing 4 drops of concentrated hydrochloric acid is heatedat reflux for 1 hr. The reaction mixture is then allowed to cool to roomtemperature, chilled in an ice bath, and the desired product whichcrystallizes is collected on a filter; yield, 6.7 g. (54.7%), M.P.173175 C. The filtrate is concentrated to provide a further amount ofcrude product; total combined yield, 65.4%. The combined product is thentwice recrystallized from ethanol, yielding the desired product in purecrystalline form, M.P. 172.5-174.5 C.

Analysis.C, 47.21; H, 6.54; CI, 11.26.

PROCEDURE 49 dissolved in ml. of 50% methanol containing 2 g. of a 10%palladium-on-carbon hydrogenation catalyst. The mixture is thenhydrogenated at a pressure of approximately 50 p.s.i.g. resulting in theabsorption of the calculated quantity of hydrogen. The catalyst isseparated and the solvent distilled from the clear reaction solution atreduced pressure. The product is obtained as a colorless oil. The oil istreated with 1 chemical equivalent of ethanolic sodium hydroxide and thesolvent and sodium chloride removed by evaporation, treatment withchloroform, and filtration. 3 3-dimethyl-l-hydroxypropyl)methanesulfonanilide is obtained as a light yellow oil on evaporation ofthe chloroform. This material is dissolved in 50 ml. of isopropanol andtreated with acetic acid, resulting in precipitation of the desiredproduct weighing 11.2 g., M.P. l49'152 C. It is twice recrystallizedfrom isopropanol 23 containing about 1% of acetic acid, resulting in thepure crystalline form of the desired product, M.P. 157- Analysis.-C,50.72; H, The foregoing procedures are applicable to the preparation ofa great number of additional compounds of the present invention bysubstitution of the appropriate starting materials therein. Table XIcontains a summary of methods for the preparation of additionalaminoalkanolsulfonanilides of the present invention by application ofthese procedures to such other starting materials as are appropriate ineach instance. The starting materials are prepared as described herein,or in some instances by methods known to the art.

The physical properties of a number of the aminoalkanolsulfonanilides ofthe present invention are listed in Table XII. The portions of thepresent disclosure which refer to the preparation of each of thesespecific compounds are listed in that table in the column entitledProcess.

Compounds of the present invention having pronounced adrenergic,fi-receptor blocking activity are 4 (2isopropylamino-l-hydroxyethyl)methanesulfonanilide,

4 [2 (t-butylamino)-1-hydroxyethyl]methanesulfonanilide, and

4 (2 methylaminod-hydroxypropyl)methanesulfonanilide and theirpharmaceutically acceptable acid addition salts. As such, they haveutility in treating a variety of degenerative diseases or physiologicabnormalities in which mulfunction of the autonomic nervous system isinvolved, for

5 example degenerative cardiovascular diseases. Dosages in 5.0 mg./k-g.are suitable.

the range of 0.02 to Among the class of compounds of this invention area number of potent inhibitors of smooth muscle activity.

2 hydroxy-5-[1-hydroxy-2-(4-methoxyphenethylamino)- 10propyl]methanesulfonanilide,

2 hydroxy 5-[1-hydroxy-2-(l-phenoxy-Z-propylamino)-,

propyl]methanesulfonanilide, and

2 hydroxy 5 (1-hydroXy-2-isopropylaminoethyl)methanesulfonanilide l5 andtheir pharmaceutically acceptable acid addition salts comprise preferredspecies exhibiting such properties. These compounds are suited asperipheral vasodilators, and as general smooth muscle .relaxants for thetreatment 20 of dysfunctions of the uterus,

bilary tract, ureters, and

intestine, and as bronchodilators; The effective dosage range is from0.01 to 1.0 mg./kg. They are active on oral administration.

While several particular embodiments of this invention invention is notto be limited cations may be made, the appended claims fall within thetrue spirit and scope of this invention.

TABLE XL-AMINOALKANOLSULFONANILIDES BY ADAPTATION OF PROCEDURES 149Entry No. Product Starting Material Procedures2-hyd1rgxy-5-(2-amino-1-hydroxyethy1)methanesulfon-2benzyloxy-s-(2-bromoacetyl)methanesulfonanilide. 30,16

am 1 e. 2-hydroxy5-(2-isopropylamino-1-hydroxyethyl)methane .do 26, 16

sulfonanilide. 2-hydroxy-5-(2-amino-1-hydroxypropyl)methanesulion-2-benzyloxy-S-(2-bromopropionyl) methanesulfonanilide, 15, 16

anilide. and dibenzylamine.2-hydroxy-5-(l-hydroxy-2-phenethylaminopropyl)-2-benzyloxy-5-(2-brom0propionyl)methanesulionanilide, 15, 16

methanesulfonanilide. and B-phenethylamine.Z-naethogygii-(2-methylamino-l-hydroxyethyl) methanesuL3-nitro-4-hydroxyacetophenone, and methyl iodide 4, 6, 8, 14, 15, 16

onan l e. 2-hydroxy-5-(2-piperidino-l-hydroxypropyl)methanesul-2-benzyloxy-542-brom0propionyl) methanesulionanilide, 15, 16

ionanilide. and piperidine.2-ehloro-4(2-isopropylamino-l-hydroxyethyl)methanesul-2-chloro-4-(Z-bromoacetyl)methanesulfonanlllde, and 19,37

tonanilide. isopropylamine.2-rnetltligxy'5-(2-amino-1-hydroxyethyl)methanesulton-3-nitro-4-hydroxyaeetophenone, and methyl lodide 4, 6, 8, 14, 306 ani e.1 2-hygoxyfig isopropy1am1ne-1hydroxypropy1) methane2-benzy1oxy-5-(2bromopropionyl)methanesultpnadilide.... 26, 16

su onam 1 e. 2-mlfltihpxyi-le2 isopropylamino1-hydr0xyethyl)methane-3-nitro-4-hydroxyacetophenone, and methyl iodide 4, 6, 8,14, 26,

s onan l e. 2-chloro-5-(2 is0propy1amino-l-hydroxyethyl)methane-2-chloro-5-(2-bromoacetyl)methanesulfonanilide, and 18, 37

sulfonanilide. isopropylamine. 4-(2-isopropylan1ino-1-hydr0xyethyl)-4-t0luenesu1ton- 4-t0luenesu1tonanilide. 10 anilide. Isopropylamine 19,37 3-(251s3propylamino-1-hydroxyethy1)-4-toluenesulton- 3-(2-bromoacety1)-4-toluen nilide, and isopropyla- 19, 37

an 1 e. mine. 2-(Z-amino-l-hydroxyethyl)methanesulionanilide2-aminoaeetophenone 1,14, 30, 372-amino-4-(2-amino-1-hydroxyethy1)methanesulionanilideu4-aeetylmethanesulfonanilide. 2, 14, 30, 162-hydroxy4-(2-methylamino-1-hydroxyethyl)methane-4-amino-3,-benzyloxyacetopheno 1, 14, 15, 16

sultonanilide. 2-l1rydroxy4(2-amino1-hydroxyethy1)methanesulionanido 1,14, 30, 32

l e. 2-hydroxy4 (2-isopropylamino-l'hydroxyethyl) methane- .do 1, 14,26, 16

sulionanili e. 4-hydroxy-3(2-methylamino-l-hydroxyethyl) methane2-hydroxyaeetophenone 2, 4, 43, 1, sulfonanilide. 14, 15, 4-hy droxy-3-(2-amino-1-hydroxyethyl) methanesulfonani- "do 2, 4, 43,

' e. 14, 30, 32 214-hydroxy-3-(2-isopropylamino-1-hydr0xyethyl)methauedo 2, 4, 43, 1,sultonanilide. 14, 26, 16 222-ehloro-4-(2-amino-l-hydroxyethyl)methanesulfonanilide. 2-ch1oroaniline1, 10, 30, 37 2-chloro-5-(2-amino-1-hyd.roxyethyl)methanesulfonanilide.3-amino-4-ch1oroacetophenone 8, 14, 30, 372-hydroxy-5-[1-hydroxy-2-(1-phenoxy-2-propylamino)- 5-(Z-bromopropionyl) -2-benzyloxymethanesul 15, 16

propyl]methanesuhonanilide. and 1-phenoxy-2-propylbenzylamine.5-[23,4-dimethoxyphenethylamino)-1-hydroxypropyl]-2-5-(2-bromopropionyl)-2-benzyloxymethanesultonanilide, 15, 16

hydroxymethanesulionanilide. and 3,4dimethoxyphenethylamine.2-hydroxy-5-[1-hydroxy-2-(4-methoxyphenethylamino)-5-(2-bromopropionyl)-2-benzyloxymethanesulfonanilide, 15, 16

[propyllrnethanesulfonanilide. and 4-methoxyphenethylamine. 5-2-(3,4-dimethoxyphenethylaxmno)-1-hydr0xyethyl]-2-5-(2-bromoacetyl)-2-benzyloxymethanesulfonanilide, and 15, 16

hydroxymethanesultonanilide. 3,4-dimethoxyphenethylamine.2-hydroxy-5-[1-hydroxy-2-(2-hydroxyethylam1no)propyl]-5-(2-bromopropionyl)2-benzyloxymethanesulionanllide, 15, 16

methanesulionanilide. and Nbenzylethanolamine. 2-hydroxy-5-[1-hydroxy-2-(4 methy1phenethylammo)- 5-(Z-bromopropionyl)-2benzyloxymethanesulfonanilide, 15, 16

propyl]methanesultonanilide. and tnlethylphenethy lamine.2-hydroxy-5-(l-hydroxy-2-phenethylam1noethyl)methane-6-(2br0m0acetyl)-2'benzyloxymethanesultonanilide, and 15, 16

sulionanilide. phenethylamine. fi-(llhhfydroirlyghenethylaminoethyl)-2-methoxymethane- 3-nitro-4-hydroxyacetophenone, and methyl iodide 4,6, 8, 14

s 01mm 1 e.

Phenethylamine 15, 16 2-benzyloxy-5-[2(4chl0rophenethylammo)-1-hydr0xy-5-(2-bromopropionyl)-2-benzyloxymethanesultonanilide, 15, 3

propyl]methanesulfonanilide. and 4-chlorophenethylamine.

3,341,584 27 28 TABLE XIL-PHYSICAL PROPERTIES OFAMINOALKANOLSUL]?ONAN11.71DES(Jor1t1nued Recrystallization AnalysisCompound Process Solvent Ml. (F 0.) (percent Infrared Absorptlon byweight) 2- hydroxy--(2-lsopr0pylam1rlo-1- Table XI, 26 entryMethylanol-isopropyl 195. 5-196. 5 C, 44. 58 2.95, 3.20, 3 38, 3.59,

hydroxyethyl)methenesulfonanillde ether. (de0.) H, 6. 56 6.21, 6.40,6.60, 7.18, hydrochloride. N, 8. 7.58, 7.75, 8.62, 8.70,

2-hydroxy-5-(2-amlno-1-hydroxy- Table XI, 3d entry Ethanol-ethylacetate. 201-202. 5 C, 40. 68 2.98, 3.20, 3.30, 6.20,

propybmethanesullonanllide hydro- (dee.) H, 5. 98 6.30, 6.60, 6.78,7.18, chloride. N, 9. 58 7.50, 8 10, 8.27, 8.70,

2-hydroxy-5-(l-hydroxy-2-phenethyl- Table XI, 4th entryEthanol-isopropyl 186-188 C, 53. 42 3.00, 3.60, 6.10, 6.60,

amlnopropyl)methanesulfonanilide ether. H, 6. 33 6.85, 7. 8, 7.60, 7.75,hydrochloride. N, 7.03 8.05, 8.70, 9.05, 10.20,

S, 7.97 13.20, 14.30. Cl, 8. 77

2-Inethqxy-5-(2-methylam1no-1- Table XI, 5th entry Aeetonitrile 166-168C, 42.16 2.80, 3.05, 3.40, 3.65,

hydroxyethyl)methanesulionanillde H, 6. 14 6.22, 6.65, 6.82, 7.13,hydrochloride. N 8.99 7.26, 7.50, 8.02, 8.65,

y D D -hY O Y- Table XI, 6th entry Ethanol 230. 5-231. 5 c, 40. 2.09,3.10, 3.40, 3.75,

propyl)methanesulfonanillde hydro- ((100.) H, 6. 92 6.21, 6.60, 6.85,7.65, chlorlde. N, 7. 62 7.73, 8.70, 9.01, 10.20,

2- hlor 4(2-isopr0py1am1no-1- Table XI, 7th entry Absolute ethanol 206.5-207. 5 C, 42.17 3.03, 3.18, 3.34, 3.53,

hydroxyetl yl)methanesulfonanillde H, r 6.03 6.47, 6.62, 6.75, 6.90,hydrochloride. C1, 20. 84 7.16, 7.50, 7.69, 7.81,

Z-meth0xY-5-( -8In1no-1-hydroxyethyl) Table XI, 8th entryMethanol-lsopropyl 177. 5-179. 5 C, 40. 53 2.95, 3.18, 3.30, 6.20,

methanesulfouanlllde hydroether. (600.) H, 5. 83 6.30, 6.60, 6.90, 7.18,chloride. N, 9. 33 7.60, 7.80, 8.68, 8.81,

-hydm5y-5-(2-1s0propy1am1no-1- Table X1, 9th entry Aeetonitrile 203.5-205. 5 c, 40. 34 2.95, 3.05, 3.35, 6.20,

v r y py et a esulfon- (dec.) 11, 6.84 6.30, 6.60, 7.18, 7.60, anilldehydrochlonde- 6, 9.58 7.72, 3.70, 9.05, 0.30,

N, 8. 21 10.17, 12.85. 2-m th0xy-5-( -l opropylsmlno-l- Table X1, 10thentry Methanol-isopropyl 216-221 C, 46. 08 2.99, 3.20, 3.38, 3.58,

hydroxyethyl)methanesulionenilide other. (dee) H, 7.08 6.20, 6. 9, 6.60,7.15, hydrochloride N, s. 04 7.58, 7.35, 8.63, 3.70,

2 p py m no-l- Table XI, 11th entry Isopropyl alcohol 194. 5-196 0, 41.72 3.00, 3.22, 3.40, 3.60,

hydroxyethyl)methanesulionanllide H, 6.02 6.40, 6.70, 7. 5, 7.55,hydroch o ide. 0 20.65 8.12, 8.65, 0.40, 0.55,

4-(2-1sop py q- -hydroxyethyl)- Table XI, 12th entry Isoproponol 189.5-100. 5 C, 55. 20 2.90, 3.37, 3.60, 6.21,

4-toluenesulfonan1lide hydro- (1100.) H, 6. 6.28, 6.33, 6.60, 6.80,chloride. 01, 9.16 6.90, 7.15, 7.52, 7.71, N, 6.90 8.17, 8.45, 8.62,9.18,

2-am1no-4-(2.methy1an1in0-1-hy6roxy- Table VI, 10th entry Ethanol,water-ether" 198-199 C, 36. 63 3.02, 3.42, 3.56, 3.90, 6.14, ethylmethanesulionam de d ((190.) H, 6.00 6. 32, 6.40, 6.69, 6.81,hydrochloride. N, 12. 28 6.98, 7.18, 7.54, 8.07,

2-am1n -4-(2-amln6-l-hydroxyethyl)- Table XI, 15th entry Methanolethylacetate. 169-170 26.83 2.92, 3.32, 3.87, 5.85, 6.24,methanesulfonanllide dihYdl'O- (096.) H, 4.44 6.41, 6.72, 6.89, 7.14,bromide. Br, 38.06 7.54, 7.98, 8.68, 8.87,

3-(21sepropylemlno-l-hydroxyethyl)- Table XI, 13th entry Isopropanol159-161 C, 55. 88 3.00, 3.21, 3.38,. 3.60, 6.30, 4-toluenesul1ononilidehydrochloride. H, 6.83 6.70, 6.80, 7.15, 7.48, 01, 9. 23 7.73, 8.09,8.63, 9.16, N, 7. 06 9.35, 9.83, 9.98, 10.27,

2-(Z-amino-l-hydroxyethyDmethane- Table XI, 14th entry Ethanol, ether186. 5-188 C, 40.80 3.34, 6.30, 6.35, 6.70, 6.76, sullonanilidehydrochloride. H, 5. 64 6.90, 7.05, 7.15, 7.55, Cl, 13.27 7.60, 8.12,8.43, 8.70, N, 10.66 9.22, 9.55, 9.63, 10.00,

-chloro-4-(2-arnino-1-hydroxyethyb- Table XI, 22nd entry- Absoluteethanol- 181-1825 0, 34.78 3.00.3.12, 3.33, 6.25, 6.68,methanesullonanlllde hydrochloether. H, 4.89 6.96, 7.15, 7.52, 8. 8,ride. C 23.52 8.33, 8.63, 9.50, 10.00,

TABLE XIIr-PHYSICAL PROPERTIES OF AMINOALKANOLSULFONANILIDES-ContinuedCompound 2-chloro-5-(2-am1n0-1-hydroxyethyl)- mgthanesulionanilidehydrochlon e.

2-hydroxy-5-[1-hydroxy-2-(l-phenoxy-2-propylamino)propyl]methanesulfonanilide hydrochloride.

5-[2-(3,4-dimethoxyphenethylamino)-l-hydroxypropyl1-2-hydroxymgthanesulfonanilide hydrochlon e.

2-hydroxy-5-[l-hydroxy-2 (4.111ethoxyphenethylamino)propylhnethanesulfonanilide hydrochloride.

5-[2- (3,4-dimethoxyphenethylamln)-l-hydroxyethyl]-2hydroxymethanesulfonanllide hydrochloride.

2-hydroxy-5-[1-hydroxy-2-(Z-hydroxyethylamino)propyHmethanesulfonanilidehydrochloride2-hydroxy-5-[1-hydroxy-2-(4-methylphenethylarm'no)propylhnethanesulionanilidehydrochloride.

2-hydroxy-5- (1-hydroxy-2-phenethylaminoethybmethanesulfonanilidehydrochloride.

- (1-hydr0xy-2-phenethy1am1noethyl)- 2-methoxymethanesnlionenilidehydrochloride.

2-benzyloxy-5-[2-(4-chlorophenethylamino)-1-hydroxy ropyl}methanesulionani 'de hydrochloride (erythro).

2-benzyloxy-5-[2-(4-chlorophenethylamino)-l-hydroxypropyl]methanesulfonanilidehydrochloride (threo isomer)2-hydroxy-5-[l-hydroxy-2-(4-methanesulfonamidophenethylamino)-propyHmethanesulmnanilide hydrochloride.

4-hydroxy-3- (l-hydroxy-Z-methylaminoethyhmethanesulfonanilidehydrochloride.

2-hydroxy-4(1-hydroxy-2-phenethylaminoethyl)methanesulfonanilidehydrochloride.

2-hydroxy-4 (l-hydroxy-Z-isopropylaminoethybmethanesulfonanilidehydrochloride.

2-hydroxy-4-(1-hydroxy- -aminoethyl)- rnethanesuhonanilidehydrochloride.

2-hydroxy-4-(l-hydroxy-z'methylaminoethyl)methanesulfonanilidehydrochloride.

3-(3-methylam1no-1-hydrox ropybmethanesulfonanilide hy r ochloride.

4- (1-hydroxy-S-methylflminopropyl)- methanesulfonanilidep-tolnenesulfonate.

4-(3-amino-1-hydroxypropyD- methanesulionanilide p-toluenesulionate.

Erythro-4-(2-isopropylamlno-1- hydroxybutyl)methanesulfonanilidehydrochloride.

3-(2-phenethylamino-l-hydroxyethyl)-4-toluenesulfonani1idehydrochloride.

Recrystallization Process Solvent M.P. C.)

Table XI, 23rd entry Isopropanol 142-144 g, 01', N;

Table XI, 24th entry Ethanolisopropanol.-- 228. 6-229. 5 C, (dec.) H, NTable XI, 25th entry Methanolisopropyl 203-204 C, ether. (dec.) 1851,

Table XI, 26th entry d0 181-183 C, 52. 68 H, 6.53 S, 7. 58 Table XI,27th entry d0 185186 C, 50. 67 (dec.) H, 6. 12 N, 6. 06 S, 7. 18 TableXI, 28th entry do 182. 5-184 C, 41. 99 H, 6.35 N, 8. 02 S, 9. 31 TableXI, 29th entry -.d0 218-219 C, 55. 03 (dec.) H, 6. 52 S, 7. 72 Table XI,30th entry do 205-205. 5 C, 52. 42 (dec.) H, 6. 13 N, 7. 05 S, 8. 28Table XI, 31st entry do 154. 5-155. 5 O, 53. (dec.) H, 6. 52 N, 6.84 S,7. 93 Table XI, 32nd entry Methanolethanol 208. 5-210 0, 56. 88 (dec.)H, 5. 79 s, 6.19

Table XI, 32nd entry Acetonitrile 178-180 g, 5;. s, 6: 24

Table XI, 33rd entry Methanolisopropyl 226-227 46.01 ether. (dec.) 5. 928. 43 12. 99 Table XI, 19th entry do 180-182 39. 77 (dec.) 5.79 9. 2110. 67 Table XI, 34th entry do 224-224. 5 52. 90 (dec.) 6. 06 7. 18 8.29 Table XI, 18th entry d0 211. 5-212. 5 44. 51 (dec.) 6. 25 8. 59 9. 98Table XI, 17th entry Isopropanol 185. 5-186. 5 38. 52 (dec.) 5. 44 9. 6711. 33 Table XI, 16th entry Methanolisopropanol" 211. 5-212 40. 76(dec.) 5. 9. 57 10. 76 Table XI, 41st entry Absolute ethanol 156-158 4%.837

. 2 12. 11 Table XI, 42nd entry d0 121. 5-123. 5 5g. 4g

. 2 14. 90 Table XI, 44th entry 95% ethanol 229-230 49. 31 5. 1 41 TableXI, 35th entry Water or isopropanol 241-243 62 (dec.) 7. 57 10. 54 TableXI, 36th entry Acatonitrlle or 164-174 61. 20 isopropanol. 6. 10 6.168.08

Infrared Absorption 1) TABLE XIL-PHYSICAL PROPERTIES OFAMINOALKANQLSULFONANILIDES-Continued Recrystallization Analysis CompoundProcess Solvent M.P. 0.) (percent 1 Infrared Absorption (,1)

by weight) 4-(sec-butylamino-l-hydroxyethyl) Table XI, 37th entry 4:1lsopropanohether 159-161 C, 48.17 2.9, .4, 6.2, 6.6, 6.85,methanesulfonanilide hydrochloride. H, 7. 15 7.15, 7.55, 8.18, 8.7.

Cl, 10. 90 4-(2-see-butylamlnojl-hydroxypropyb- Table XI, 38th entry :1isopropanol: 190. 5-202. 5 C, 49.84 2.95, 3.35, 6.2, 6.6, 6.83,methanesulfonanillde hydrochloride. water 1g, 7. 7.5, 8.15, 8,67.4-(2-isopropylamlno-1-hydroxypropyl)- Table XI, 39th entry 1:1 ether:95%228-229 C, 48. 60 2 95, 8 35, 6 2, 6. 6 8, methanesulfonam'lidehydroethanol. (dec.) H, 7. 40 7. 7 55, 8.15, 8.65 chloride. 01, 10. 894-(2amino-l-hydroxyethyD-4- Table XI, 40th entry Ethanol 178-179. 5 C,55. 49 2.9, 3.3, 6.2, 6.6, toluenesulionanilide 4-toluene- (dec.) H, 5.57 7.15, 7.5, 8 6 8.9. sulionate. S, 13. 364-(2-methylamlno-1-hydroxyethyl)-p- Table XI, 47th entry Absoluteethanol 2. 5. 5-217 C, 54. 11 3.0, 3. 6. 6.6, 6.8, toluenesulfonanilldehydrochloride. (dec) H, 6.02 7.15, 7.52, 8.6, 0.2,

Cl, 9.84 10.6, 12.2 3-(2-amlno-1-hydroxyethyl)-4- Table XI, 48th entry.do 148-152 C, 58.80 2.95, 6.25, 6.65, 7.7, 8.65, toluenesullonanilide.H, 5. 92 8. 9.2, 12.3, 14.2.

N, 9. S, 10. 46 Erythro-4-(2-methylamlno-1-hydroxy- Table XI, 49th entryEthanol-ether 234-235 C, 46. 43 3.1, 3.3, 6.22, 6.38, 6.62,butyl)rnethanesulfonanllide (dec.) H, 6. 79 6.85, 7 ,08, 7.53, 8.3;hydrochloride. 8, 10. 65 8.67, 9.4, 10.25, 11.0,

11.2, and 13.0.

4-[1-hydroxy-2-(lsopropylarnino)- Table XI, 50th entry IsopropanoL. 148.5-151 0, 51.26 2.95, 3,12, 3.40, 6.21,

ethyl]butanesulfonanllide. H, 7. 6.61, 6. 2, 7.17, 7.51,

and 10.74.

3-(2-amlno-l-hydroxyethyl)butane- Table XI, 52nd entry Isopropanol-ether121-122. 5 C, 52. 74 2.94, 3.20, 3,40, 6.22,

sulfonanlllde. H, 7. 39 6.78, 7.10, 7.51, 8.09, N, 10.21 8.73, 9.07,9.95, 10,11.

11.25, 12.78, and .20.

4-[2-(tort-butylamlno)-1-l1ydroxy- Table XI, 53rd entryIsopropanol-ethanol- 166-168 C, 42. 46 2,96, 3.08, 3.29, 3.38,

ethyl1methanesulfonan1lide ether. H, 6. 25 6.21, 6.61, 6.89, 7.23,hydrobromlde. N, 7. 53 7.57, 8.70, 9.26, 10.

and 12.83.

Erythr04-(l-hydrory-2-methyl- Table VI, 7th entry Aqueous ethanol165-168. 5 C, 55. 31 3.05, 3.12, 3.39, 3.56,aminopropyl)-p-toluene5ul1onani1lde H, 6. 11 6.23, 6. 9, 6.62, 6.80,hydrochloride. 0 9.29 7.13, 7.48, 7 .52, 8.19, 8.43, 8.60, 9.18, 9.51,9.81, 10.00, 10.82, 11.71, 12.29, and 12.81.

3-[1-hydroxy-2-(isopropylamino)- Table XI, 54th entry Isopropanol 132.5-135. 5 C, 54.82 2.97, 3.24, 3.30, 3,41,,

ethyllbutanesulfonanilide acetate. H, 8.31 3.52, 6. 4, 6,40, 6.80, N, 7.51 7.14, 7.52, 8.12, 8.73, 9.30.

2-methyl-5-(ll-methylamino-l-hydroxy- Table VI, 12th entry Ethanol 141.5-146 C, 44. 3.13. 3.23, 3.38, 3.62,

ethyl)mothanesulfonanilide H, 6. 55 6.37, 6. 4, 6.86, 6.93,hydrochloride. 0 12. 15 7.08, 7.62, 7.93, 8.69,

A great number of haloalkyl ketone intermediates of 50pentamethyleneimine the type represented by Formula II have beendisclosed indoline herein. Refer especially to Procedures 10 and 14 andto 1-carboxycyclopentylamine Tables 11, 1V, VI, and IX. There are listedbelow a numcyclohexylamine ber of representative amines of the formula31 which may be condensed with these haloalkyl ketone intermediatessubstantially as described in Procedures 15, 18, or 26, or by relatedmethods known to the art. The

formula R4 refers to the definition given above. The resultingaminoalkyl ketones (Formula III) may then be reduced to provide thephenalkanolamines of Formula I (Z CHOH) substantially as disclosed inProcedures 16, 32, 37, and 49.

2-aminoindane 2-arninobicyclo[2,2,2] octane Z-aminomethylbicyclo[2,2,2]octane 3-azabicyclo[3,2,2]nonane 3-aminocyclohexl-ene a-aminoisobutyricacid N-(Z-aminoethyl) pyrrole N- (Z-aminoethyl) piperazine2-phenylcyclopropylamine N-benzyl-4-aminopiperidine l-aminoindane 3-phenylpropy1amine 3-aminoazabicyclo [2,2,2] octane2-amino-l-phenylprop-l-ol l-aminoadamantane l-aminobicyclo[2,2,1]hcptane 2-amino-2-methyll-propanol 2-amin0pentaneZ-hydroxy-Z-phenethyl amine cyclop entylmethylamine cyclopent-2-en-I-yhnethylamine 2-aminobicyclo[2,2,1]-5-heptene Z-arnino-l 1210p anolfi- (p-chlorophenyl) -a,a-dimethylethylamine 2- (p-chlorophenyl)ethylamine cyclopropylarnine 33 1,3-dimethylbutylamine1,4-dimethylpentylamine 2,2-diphenylethylamineZ-amino-1,3-dihydroxy-2-ethylpropane 2-amino-3,3-dimethylbutanebenzhydrylamine 2-aminoheptane 2-amino-l-methoxypropaneaminomethylcyclopropane 2-amino-2-methyl-1,3-propanediol2-ethylhexylamine hexylamine 3-methoxypropylamine a-methylbenzylamineallylamine methallylamine Z-aminomethylbicyclo 2,2, 1] -5 -heptenepyrrolidine pipezidine hexamethyleneimine thiomorpholine morpholinepiperazine nor-tropane perhydroisoquinoline tetrahydroisoquinolineperhydroquinoline tetrahydroquinoline Z-aminopyridine anilinenapthylamine styrylamine What is claimed is:

1. A compound selected from the group consisting of (a) the substance ofFormula I X Formula I group having 1 to 4 carbon atoms through from 1 to2 carbon atoms,

R is selected from the group consisting of hydrogen,

alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl,cycloalkenylalkyl, bicycloalkyl, tricycloalkyl, bicycloalkenyl,bicycloalkylalkyl, bicycloalkenylalkyl, aryl, phenylalkyl,phenylalkenyl, phenoxyalkyl, heteromonocyclic, heteromonocycloalkyl, andheterobicyclic each containing up to 10 carbon atoms and having up totwo substituents selected from thegroup consisting of hydroxyl,carboxyl, amino, lower alkoxy, benzyloxy, halogen, lower alkyl,methylenedioxy, and R SO NH each of said heteromonocyclic,heteromonocycloalkyl and heterobicyclic containing a nitrogen atom andup to one additional heteroatom selected from the group of oxygen,nitrogen and sulfur, and wherein each of said lower alkyl and loweralkoxy groups has up to 4 carbon atoms, (b) the acid addition salt of(a), and the metal salt of (a).

2. A compound as claimed in claim 1 wherein Alk is --CH X and R arehydrogen, Z is CHOH, and R and R are methyl.

3. 3 (2-methylamino-l-hydroxyethyl)methanesulfonanilide.

4. 3 (Z-methylamino-l-hydroxyethyl)methanesulfonanilidemethanesulfonate.

5. 3 (Z-methylamino-l-hydroxyethyl)methanesulfonanilide hydrochloride.

6. The sodium salt of3-(2-methylamino-l-hydroxyethyl)methanesulfonanilide.

7. A compound as claimed in claim 1 wherein Alk is CH X and R arehydrogen, Z is CHOH, R is methyl, and R is isopropyl.

8. 4 (2 isopropylamino-l-hydroxyethyl)methanesulfonanilide.

9. 4 (2 isopropylamino-l-hydroxyethyl)methanesulfonanilidehydrochloride.

10. A compound as claimed in claim 1 wherein Alk is X and R arehydrogen, Z is CHOH, and R and R are methyl.

11. 4 (2 methylamino-l-hydroxypropyDmethanesulfonaniilde.

12. 4 (2 methylamino-l-hydroxypropyl)methanesulfonanilide hydrochloride.

13. A compound as claimed in claim 1 wherein Alk is X is OH, R ismethyl, R is hydrogen, Z is CHOH, and R is 4-methoxyphenethyl.

14. 2 hydroXy-5-[l-hydroxy-Z-(4-methoXyphenethy1- amino) propyl]methanesulfonanilide.

15. 2 hydroxy5-[1-hydroxy-2-(4-methoxyphenethylamino)propyl]methanesulfonanilidehydrochloride.

16. A compound as claimed in claim 1 wherein Alk is lHCHa X is OH, R ismethyl, R is hydrogen, Z is CHOH, and R is l-phenoxy-Z-propyl.

17. 2 hydroxy5-[2-(l-phenoxy-2-propylamino)-lhydroXypropyl]methanesulfonanilide.

18. 2 hydroxy5-[2-(l-phenoxy-Z-propylamino)-lhydroxypropyl]methanesulfonanilidehydrochloride.

19. A compound as claimed in claim 1 wherein Alk is CH X is OH, R ismethyl, R is hydrogen, Z is CHOH, and R is isopropyl.

20. 2 hydroxy 5(2-isopropylamino-1-hydroxyethyl)- methanesulfonanilide.

21. 2 hydroxy 5-(2-isopropylamino-l-hydroxyethyl)- meth-anesulfonanilidehydrochloride.

22. A compound as claimed in claim 1 wherein Alk is CH X is hydrogen, Zis C,:O, R is benzyl, and R and R are methyl.

23. 3 (2 benzylmethylaminoacetyl)methanesulfonanilide.

24. 4-(2-dibenzy1aminoaeety1) methaneusifonanilide.

25. 3-(2-an1inoacety1)methanesulfonanilide,

26. A compound as claimed in claim 1 wherein Alk is --CH;, X and R arehydrogen, Z is CHOH, R is methyl, and R is tertiary-buty1.

27. 4 [2 (tert-butylamino)-1-hydr0xyethyl]methanesulfonanilide.

28. 4 [2 (tert-butylamino)-1-hydroxyethy1]methanesulfonanilidehydrobromide.

36 References Cited.

UNITED STATES PATENTS 3,162,684 12/1964 Frick et a1. 260-556 3,178,3394/1965 Frick et a1. 260-556 UNITED STATES PATENT OFFICE CERTIFICATE OFCORRECTION Patent No. 3,341,584 September 12, 1967 Aubrey A. Larsen eta1.

It is hereby certified that error appears in the above numbered patentrequiring correction and that the said Letters Patent should read ascorrected below.

Column 1, line 58, for "polycycloalkenylalky" read polycycloalkenylalkylline 59, for "arloxyalkyl" read aryloxyalkyl column 2, lines 41 and 42,the formula should appear as shown below instead of as in the patent:

C H CH CH CH- CH3 line 66, for "phenethanolamides" readphenethanolamines column 3, line 18 after "is" insert a e formula IIshould appear as shown below instead of as in the patent:

NHS02R1 /R A HN CO Alk R same column 3, line 64, for "product." readproduct, column 4, line 52, for "ensulfonate" read enesulfonate column5, line 68, for "90 ml." read 900 ml. column 6, line 24, for "(1949)"read (1947) column 7, line 15, for "knitropropiophenone" read3-nitropropiophenone line 55, for "disulfied" read disulfide column 8,line 73, for "is" read as column 12, footnote 3, opposite Analysis, line1 thereof, for "abInfrared sorption" read Infrared absorption column 14,line 2, for "(0.02 mole)" read (0.2 mole] column 20, line 38, for"hylrochloride" read hydrochloride column 21, line 15, for"3benzyloxyacetophenone" read 3-benzy1oxyacetophenone column 24, line20, for "bilary" read biliary columns 23 and 24 TABLE XI Entry No 9 for"2-isopropylami read 2-isopropylamino same table, Entry No 25 for "5-[2-3 ,4" read S-[2(3,4- columns 25 and 26, TABLE XII, last column, thirdgroup of numbers, line 1 thereof, for "3,00"

read 3.00 same group of numbers, line 2 thereof, for

"8 .80" read 6.80 columns 3 l and 3 2, TABLE XII under the headingCompound, first item, line 1 thereof, for "4- (s ec-butylamino-" read 4[2-sec -butylaminosame heading, second item, line 1 thereof, for"4-(2-secbutylaminojl-" read 4-[2-sec-butylamino-lsame table,

last column, second group of numbers, line 2 thereof, for "8,67" read8.67 same column, seventh group of numbers, line 2 thereof, for "7,08"read 7.08 same column, eighth group of numbers, line 3 thereof, for"8,19" read 8.19 same column, ninth group of numbers, line 1 thereof,for "3,40" read 3.40 same group of numbers, line 3 thereof, for "10,11"read 10.11 same column, tenth group of numbers, line 1 thereof, for"2,96" read 2.96 same column, twelfth group of numbers, line 2 thereof,for "6,40" read 6.40

Signed and sealed this 1st day of October 1968.

(SEAL) Attest:

EDWARD M.FLETCHER,JR. EDWARD J. BRENNER Attesting Officer Commissionerof Patents

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF (A) THE SUBSTANCE OFFORMULA I